Compounds and methods for the targeted degradation of interleukin-1 receptor-associated kinase 4 polypeptides

ABSTRACT

The present disclosure relates to bifunctional compounds, which find utility as modulators of Interleukin-1 Receptor-Associated Kinase 4 (IRAK-4); the target protein). In particular, the present disclosure is directed to bifunctional compounds, which contain on one end a Von Hppel-Lindau, cereblon, ligand which binds to the E3 ubiquitin ligase and on the other end a moiety which binds the target protein, such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of target protein. The present disclosure exhibits a broad range of pharmacological activities associated with degradation/inhibition of target protein. Diseases or disorders that result from aggregation or accumulation of the target protein are treated or prevented with compounds and compositions of the present disclosure.

RELATED APPLICATIONS

The present disclosure claims priority to U.S. Provisional PatentApplication No. 62/587,799, filed 17 Nov. 2017, titled COMPOUNDS ANDMETHODS FOR THE TARGETED DEGRADATION OF INTERLEUKIN-1RECEPTOR-ASSOCIATED KINASE 4 POLYPEPTIDES, which is incorporated hereinby reference in its entirety for all purposes.

INCORPORATION BY REFERENCE

U.S. patent application Ser. No. 15/230,354, filed on Aug. 5, 2016,published as U.S. Patent Application Publication No. 2017/0065719; andU.S. patent application Ser. No. 15/206,497 filed 11 Jul. 2016,published as U.S. Patent Application Publication No. 2017/0008904; andU.S. patent application Ser. No. 15/209,648 filed 13 Jul. 2016,published as U.S. Patent Application Publication No. 2017/0037004; andU.S. patent application Ser. No. 15/730,728, filed on Oct. 11, 2017,published as U.S. Patent Application Publication No. 2018/0099940; andU.S. patent application Ser. No. 14/686,640, filed on Apr. 14, 2015,published as U.S. Patent Application Publication No. 2015/0291562; andU.S. patent application Ser. No. 14/792,414, filed on Jul. 6, 2015,published as U.S. Patent Application Publication No. 2016/0058872; andU.S. patent application Ser. No. 14/371,956, filed on Jul. 11, 2014,published as U.S. Patent Application Publication No. 2014/0356322; andU.S. patent application Ser. No. 15/074,820, filed on Mar. 18, 2016,published as U.S. Patent Application Publication No. 2016/0272639; andU.S. patent application Ser. No. 15/885,671, filed Jan. 31, 2018,published as U.S. Patent Application Publication No. 2018/0215731 A1;and International Patent Application No. PCT/US2016/023258, filed Mar.18, 2016, published as International Patent Application Publication No.WO2016/149668, are incorporated herein by reference in their entirety.Furthermore, all references cited herein are incorporated by referenceherein in their entirety.

FIELD OF THE INVENTION

The description provides bifunctional compounds comprising a targetprotein binding moiety and a E3 ubiquitin ligase binding moiety, andassociated methods of use. The bifunctional compounds are useful asmodulators of targeted ubiquitination, especially with respect toInterleukin-1 receptor-associated kinases-4 (IRAK-4), which is degradedand/or otherwise inhibited by bifunctional compounds according to thepresent disclosure.

BACKGROUND

Most small molecule drugs bind enzymes or receptors in tight andwell-defined pockets. On the other hand, protein-protein interactionsare notoriously difficult to target using small molecules due to theirlarge contact surfaces and the shallow grooves or flat interfacesinvolved. E3 ubiquitin ligases (of which hundreds are known in humans)confer substrate specificity for ubiquitination, and therefore, are moreattractive therapeutic targets than general proteasome inhibitors due totheir specificity for certain protein substrates. The development ofligands of E3 ligases has proven challenging, in part due to the factthat they must disrupt protein-protein interactions. However, recentdevelopments have provided specific ligands which bind to these ligases.For example, since the discovery of nutlins, the first small molecule E3ligase inhibitors, additional compounds have been reported that targetE3 ligases but the field remains underdeveloped. For example, since thediscovery of Nutlins, the first small molecule E3 ligase mouse doubleminute 2 homolog (MDM2) inhibitors, additional compounds have beenreported that target MDM2 (i.e., human double minute 2 or HDM2) E3ligases (J. Di, et al. Current Cancer Drug Targets (2011), 11(8),987-994).

Tumor suppressor gene p53 plays an important role in cell growth arrestand apoptosis in response to DNA damage or stress (A. Vazquez, et al.Nat. Rev. Drug. Dis. (2008), 7, 979-982), and inactivation of p53 hasbeen suggested as one of the major pathway for tumor cell survival (A.J. Levine, et al. Nature (2000), 408, 307-310). In cancer patients,about 50% were found with p53 mutation (M. Hollstein, et al. Science(1991), 233, 49-53), while patients with wild type p53 were often foundp53 down regulation by MDM2 through the protein-protein interaction ofp53 and MDM2 (P. Chene, et al. Nat. Rev. Cancer (2003), 3, 102-109).Under normal cell condition without oncogenic stress signal, MDM2 keepsp53 at low concentration. In response to DNA damage or cellular stress,p53 level increases, and that also causes increase in MDM2 due to thefeedback loop from p53/MDM2 auto regulatory system. In other words, p53regulates MDM2 at the transcription level, and MDM2 regulates p53 at itsactivity level (A. J. Levine, et al. Genes Dev. (1993) 7, 1126-1132).

First, MDM2 binds to N-terminal domain of p53 and blocks expression ofp53-responsive genes (J. Momand, et al. Cell (1992), 69, 1237-1245).Second, MDM2 shuttles p53 from nucleus to cytoplasm to facilitateproteolytic degradation (J. Roth, et al. EMBO J. (1998), 17, 554-564).Lastly, MDM2 carries intrinsic E3 ligase activity of conjugatingubiquitin to p53 for degradation through ubiquitin-dependent 26sproteasome system (UPS) (Y. Haupt, et al. Nature (1997) 387, 296-299).As such, because MDM2 functions as E3 ligase, recruiting MDM2 to adisease causing protein and effectuating its ubiquitination anddegradation is an approach of high interest for drug discovery.

One E3 ligase with exciting therapeutic potential is the vonHippel-Lindau (VHL) tumor suppressor, the substrate recognition subunitof the E3 ligase complex VCB, which also consists of elongins B and C,Cul2 and Rbx1. The primary substrate of VHL is Hypoxia Inducible Factor1α (HIF-1α), a transcription factor that upregulates genes such as thepro-angiogenic growth factor VEGF and the red blood cell inducingcytokine erythropoietin in response to low oxygen levels. The firstsmall molecule ligands of Von Hippel Lindau (VHL) to the substraterecognition subunit of the E3 ligase were generated, and crystalstructures were obtained confirming that the compound mimics the bindingmode of the transcription factor HIF-1α, the major substrate of VHL.

Cereblon is a protein that in humans is encoded by the CRBN gene. CRBNorthologs are highly conserved from plants to humans, which underscoresits physiological importance. Cereblon forms an E3 ubiquitin ligasecomplex with damaged DNA binding protein 1 (DDB1), Cullin-4A (CUL4A),and regulator of cullins 1 (ROC 1). This complex ubiquitinates a numberof other proteins. Through a mechanism which has not been completelyelucidated, cereblon ubquitination of target proteins results inincreased levels of fibroblast growth factor 8 (FGF8) and fibroblastgrowth factor 10 (FGF10). FGF8 in turn regulates a number ofdevelopmental processes, such as limb and auditory vesicle formation.The net result is that this ubiquitin ligase complex is important forlimb outgrowth in embryos. In the absence of cereblon, DDB1 forms acomplex with DDB2 that functions as a DNA damage-binding protein.

Inhibitors of Apotosis Proteins (IAPs) are a protein family involved insuppressing apoptosis, i.e. cell death. The human IAP family includes 8members, and numerous other organisms contain IAP homologs. IAPs containan E3 ligase specific domain and baculoviral IAP repeat (BIR) domainsthat recognize substrates, and promote their ubiquitination. IAPspromote ubiquitination and can directly bind and inhibit caspases.Caspases are proteases (e.g. caspase-3, caspase-7 and caspace-9) thatimplement apoptosis. As such, through the binding of caspases, IAPsinhibit cell death. However, pro-apoptotic stimuli can result in therelease of mitochondrial proteins DIABLO (also known as secondmitrochondria-derived activator of caspases or SMAC) and HTRA2 (alsoknown as Omi). Binding of DIABLO and HTRA2 appears to block IAPactivity.

SMAC interacts with essentially all known IAPs including XIAP, c-IAP1,c-IAP2, NIL-IAP, Bruce, and survivin. The first four amino acids (AVPI)of mature SMAC bind to a portion of IAPs, which is believed to beessential for blocking the anti-apoptotic effects of IAPs.

Interleukin-1 (IL-1) Receptor-Associated Kinase-4 (IRAK-4) is aserine/threonine kinase enzyme that plays an essential role in signaltransduction by Toll/IL-1 receptors (TIRs). Diverse IRAK enzymes are keycomponents in the signal transduction pathways mediated by interleukin-1receptor (IL-1R) and Toll-like receptors (TLRs) (Janssens, S, et al.Mol. Cell. 11(2), 2003, 293-302). There are four members in themammalian IRAK family: IRAK-1, IRAK-2, IRAK-M and IRAK-4. These proteinsare characterized by a typical N-terminal death domain that mediatesinteraction with MyD88-family adaptor proteins and a centrally locatedkinase domain. Upon recruitment of MyD88 and IRAK4 to theToll-interleukin domain, activation leads to phosphorylation of IRAK1and/or IRAK2 leading to engagement of TRAF6. Subsequent signalingresults in activation of NF-kB and the release of various cytokines andchemokines. The MYD88 L265P mutation occurring in 91% Waldenstrom'smacroglobulinemia, 29% ABC DLBCL, 9% MALT lymphomas, and 3% CLLcoordinates a constitutively active signalosome in which IRAK4-mediatedphosphorylation of IRAK1 promotes the assembly of additional signalingproteins driving survival in these cancers.

The IRAK proteins, as well as MyD88, have been shown to play a role intransducing signals other than those originating from IL-1R receptors,including signals triggered by activation of IL-18 receptors (Kanakaraj,et al. J. Exp. Med. 189(7), 1999, 1129-38) and LPS receptors (Yang, etal., J. Immunol. 163(2), 1999, 639-643). Out of four members in themammalian IRAK family, IRAK-4 is considered to be the “master IRAK”.Under overexpression conditions, all IRAKs can mediate the activation ofnuclear factor-.kappa.B (NF-κB) and stress-induced mitogen activatedprotein kinase (MAPK)-signaling cascades. However, only IRAK-1 andIRAK-4 have been shown to have active kinase activity. While IRAK-1kinase activity could be dispensable for its function in IL-1-inducedNF-.kappa.B activation (Kanakaraj et al, J. Exp. Med. 187(12), 1998,2073-2079) and (Li, et al. Mol. Cell. Biol. 19(7), 1999, 4643-4652),IRAK-4 requires its kinase activity for signal transduction [(Li S, etal. Proc. Natl. Acad. Sci. USA 99(8), 2002, 5567-5572) and (Lye, E etal, J. Biol. Chem. 279(39); 2004, 40653-8)]. Given the central role ofIRAK4 in Toll-like/IL-1R signalling and immunological protection, IRAK4inhibitors have been implicated as valuable therapeutics in inflammatorydiseases, sepsis and autoimmune disorders (Wietek C, et al, Mol. Interv.2: 2002, 212-215).

Mice lacking IRAK-4 are viable and show complete abrogation ofinflammatory cytokine production in response to IL-1, IL-18 or LPS(Suzuki et al. Nature, 416(6882), 2002, 750-756). Similarly, humanpatients lacking IRAK-4 are severely immunocompromised and are notresponsive to these cytokines (Medvedev et al. J. Exp. Med., 198(4),2003, 521-531 and Picard et al. Science 299(5615), 2003, 2076-2079).Knock-in mice containing inactive IRAK4 were completely resistant tolipopolysaccharide- and CpG-induced shock (Kim T W, et al. J. Exp. Med204(5), 2007, 1025-36) and (Kawagoe T, et al. J. Exp. Med. 204(5): 2007,1013-1024) and illustrated that IRAK4 kinase activity is essential forcytokine production, activation of MAPKs and induction of NF-κBregulated genes in response to TLR ligands (Koziczak-Holbro M, et al. J.Biol. Chem. 282(18): 2007; 13552-13560). Inactivation of IRAK4 kinase(IRAK4 KI) in mice leads to resistance to EAE due to reduction ininfiltrating inflammatory cells into CNS and reduced antigen specificCD4+ T-cell mediated IL-17 production (Staschke et al. The Journal ofImmunology, 183(1), 2009, 568-577).

Bifunctional compounds such as those that are described in U.S. PatentApplication Publication Nos 2015-0291562 and 2014-0356322 (incorporatedherein by reference), function to recruit endogenous proteins to an E3ubiquiuin ligase for degradation. In particular, the publicationsdescribe bifunctional or proteolysis targeting chimeric (PROTAC)compounds, which find utility as modulators of targeted ubiquitinationof a variety of polypeptides and other proteins, which are then degradedand/or otherwise inhibited by the bifunctional compounds.

An ongoing need exists in the art for effective treatments for diseaseassociated with overexpression or aggregation of IRAK-4. However,non-specific effects, and the inability to target and modulate IRAK-4,remain as obstacles to the development of effective treatments. As such,small-molecule therapeutic agents that target IRAK-4 and that leverageor potentiate VHL's, cereblon's, MDM2's, and IAPs' substrate specificitywould be very useful.

SUMMARY

The present disclosure describes bifunctional compounds which functionto recruit endogenous proteins to an E3 ubiquitin ligase fordegradation, and methods of using the same. In particular, the presentdisclosure provides bifunctional or proteolysis targeting chimeric(PROTAC) compounds, which find utility as modulators of targetedubiquitination of a variety of polypeptides and other proteins, whichare then degraded and/or otherwise inhibited by the bifunctionalcompounds as described herein. An advantage of the compounds providedherein is that a broad range of pharmacological activities is possible,consistent with the degradation/inhibition of targeted polypeptides fromvirtually any protein class or family. In addition, the descriptionprovides methods of using an effective amount of the compounds asdescribed herein for the treatment or amelioration of a diseasecondition, such as cancer, inflammatory diseases/disorders,neurodegenerative diseases, as well as cardiovasculardiseases/disorders.

As such, in one aspect the disclosure provides bifunctional or PROTACcompounds, which comprise an E3 ubiquitin ligase binding moiety (i.e., aligand for an E3 ubquitin ligase or “ULM” group), and a moiety thatbinds a target protein (i.e., a protein/polypeptide targeting ligand or“PTM” group) such that the target protein/polypeptide is placed inproximity to the ubiquitin ligase to effect degradation (and inhibition)of that protein. In a preferred embodiment, the ULM (ubiquitinationligase modulator) can be Von Hippel-Lindau E3 ubiquitin ligase (VHL)binding moiety (VLM), or a cereblon E3 ubiquitin ligase binding moiety(CLM), or a mouse double minute 2 homolog (MDM2) E3 ubiquitin ligasebinding moiety (MLM), or an IAP E3 ubiquitin ligase binding moiety(i.e., a “ILM”). For example, the structure of the bifunctional compoundcan be depicted as:

The respective positions of the PTM and ULM moieties (e.g., VLM, CLM,MLM or ILM) as well as their number as illustrated herein is provided byway of example only and is not intended to limit the compounds in anyway. As would be understood by the skilled artisan, the bifunctionalcompounds as described herein can be synthesized such that the numberand position of the respective functional moieties can be varied asdesired.

In certain embodiments, the bifunctional compound further comprises achemical linker (“L”). In this example, the structure of thebifunctional compound can be depicted as:

where PTM is a protein/polypeptide targeting moiety, L is a linker,e.g., a bond or a chemical group coupling PTM to ULM, and ULM is a IAPE3 ubiquitin ligase binding moiety, or a Von Hippel-Lindau E3 ubiquitinligase (VHL) binding moiety (VLM), or a cereblon E3 ubiquitin ligasebinding moiety (CLM), or a mouse double minute 2 homolog (MDM2) E3ubiquitin ligase binding moiety (MLM).

For example, the structure of the biofunctional compound can be depictedas:

wherein: PTM is a protein/polypeptide targeting moiety; “L” is a linker(e.g. a bond or a chemical linker group) coupling the PTM and at leastone of VLM, CLM, MLM, ILM, or a combination thereof; VLM is VonHippel-Lindau E3 ubiquitin ligase binding moiety that binds to VHL E3ligase; CLM is cereblon E3 ubiquitin ligase binding moiety that binds tocereblon; MLM is an MDM2 E3 ubiquitin ligase binding moiety; and ILM isa IAP binding moiety which binds to IAP;

In certain preferred embodiments, the ILM is an AVPI tetrapeptidefragment. As such, in certain additional embodiments, the ILM of thebifunctional compound comprises the amino acids alanine (A), valine (V),proline (P), and isoleucine (I) or their unnatural mimetics,respectively. In additional embodiments, the amino acids of the AVPItetrapeptide fragment are connected to each other through amide bonds(i.e., —C(O)NH— or —NHC(O)—).

In certain embodiments, the compounds as described herein comprisemultiple independently selected ULMs, multiple PTMs, multiple chemicallinkers or a combination thereof.

In certain embodiments, ILM comprises chemical moieties such as thosedescribed herein.

In additional embodiments, VLM can be hydroxyproline or a derivativethereof. Furthermore, other contemplated VLMs are included in U.S.Patent Application Pub. No. 2014-03022523, which as discussed above, isincorporated herein in its entirety.

In an embodiment, the CLM comprises a chemical group derived from animide, a thioimide, an amide, or a thioamide. In a particularembodiment, the ehcmical group is a phthalimido group, or an analog orderivative thereof. In a certain embodiment, the CLM is thalidomide,lenalidomide, pomalidomide, analogs thereof, isosteres thereof, orderivatives thereof. Other contemplated CLMs are described in U.S.Patent Application Publication US 2015-0291562, which is incorporatedherein in its entirety.

In certain embodiments, MLM can be nutlin or a derivative thereof.Furthermore, other contemplated MLMs are included in U.S. patentapplication Ser. No. 15/206,497 filed 11 Jul. 2016, which as discussedabove, is incorporated herein in its entirety. In certain additionalembodiments, the MLM of the bifunctional compound comprises chemicalmoieties such as substituted imidazolines, substitutedspiro-indolinones, substituted pyrrolidines, substituted piperidinones,substituted morpholinones, substituted pyrrolopyrimidines, substitutedimidazolopyridines, substituted thiazoloimidazoline, substitutedpyrrolopyrrolidinones, and substituted isoquinolinones.

In additional embodiments, the MLM comprises the core structuresmentioned above with adjacent bis-aryl substitutions positioned as cis-or trans-configurations.

In certain embodiments, “L” is a bond. In additional embodiments, thelinker “L” is a connector with a linear non-hydrogen atom number in therange of 1 to 20. The connector “L” can contain, but not limited to thefunctional groups such as ether, amide, alkane, alkene, alkyne, ketone,hydroxyl, carboxylic acid, thioether, sulfoxide, and sulfone. The linkercan contain aromatic, heteroaromatic, cyclic, bicyclic and tricyclicmoieties. Substitution with halogen, such as Cl, F, Br and I can beincluded in the linker. In the case of fluorine substitution, single ormultiple fluorines can be included.

In certain embodiments, VLM is a derivative of trans-3-hydroxyproline,where both nitrogen and carboxylic acid in trans-3-hydroxyproline arefunctionalized as amides.

In certain embodiments, CLM is a derivative of piperidine-2,6-dione,where piperidine-2,6-dione can be substituted at the 3-position, and the3-substitution can be bicyclic hetero-aromatics with the linkage as C—Nbond or C—C bond. Examples of CLM can be, but not limited to,pomalidomide, lenalidomide and thalidomide and their derivatives.

In an additional aspect, the description provides therapeuticcompositions comprising an effective amount of a compound as describedherein or salt form thereof, and a pharmaceutically acceptable carrier.The therapeutic compositions modulate protein degradation in a patientor subject, for example, an animal such as a human, and can be used fortreating or ameliorating disease states or conditions which aremodulated through the degraded protein. In certain embodiments, thetherapeutic compositions as described herein may be used to effectuatethe degradation of proteins of interest for the treatment oramelioration of a disease, e.g., cancer, autoimmune diseases/disorder,and/or inflammatory diseases/disorders. In yet another aspect, thepresent disclosure provides a method of ubiquitinating/degrading atarget protein in a cell. In certain embodiments, the method comprisesadministering a bifunctional compound as described herein comprising anILM and a PTM, a PTM and a VLM, or a PTM and a CLM, or a PTM and a MLM,preferably linked through a linker moiety, as otherwise describedherein, wherein the VLM/ILM/CLM/MLM is coupled to the PTM through alinker to target protein that binds to PTM for degradation. Similarly,wherein PTM is coupled to VLM or CLM or MLM or ILM through a linkger totarget a protein or polypeptide for degradation. Degradation of thetarget protein will occur when the target protein is placed in proximityto the E3 ubiquitin ligase, thus resulting in degradation/inhibition ofthe effects of the target protein and the control of protein levels. Thecontrol of protein levels afforded by the present disclosure providestreatment of a disease state or condition, which is modulated throughthe target protein by lowering the level of that protein in the cells ofa patient.

In still another aspect, the description provides methods for treatingor ameliorating a disease, disorder or symptom thereof in a subject or apatient, e.g., an animal such as a human, comprising administering to asubject in need thereof a composition comprising an effective amount,e.g., a therapeutically effective amount, of a compound as describedherein or salt form thereof, and a pharmaceutically acceptable carrier,wherein the composition is effective for treating or ameliorating thedisease or disorder or symptom thereof in the subject.

In another aspect, the description provides methods for identifying theeffects of the degradation of proteins of interest in a biologicalsystem using compounds according to the present disclosure.

The preceding general areas of utility are given by way of example onlyand are not intended to be limiting on the scope of the presentdisclosure and appended claims. Additional objects and advantagesassociated with the compositions, methods, and processes of the presentdisclosure will be appreciated by one of ordinary skill in the art inlight of the instant claims, description, and examples. For example, thevarious aspects and embodiments of the disclosure may be utilized innumerous combinations, all of which are expressly contemplated by thepresent description. These additional aspects and embodiments areexpressly included within the scope of the present disclosure. Thepublications and other materials used herein to illuminate thebackground of the invention, and in particular cases, to provideadditional details respecting the practice, are incorporated byreference.

BRIEF DESCRIPTION OF THE DRAWINGS

The accompanying drawings, which are incorporated into and form a partof the specification, illustrate several embodiments of the presentinvention and, together with the description, serve to explain theprinciples of the invention. The drawings are only for the purpose ofillustrating an embodiment of the invention and are not to be construedas limiting the invention. Further objects, features and advantages ofthe invention will become apparent from the following detaileddescription taken in conjunction with the accompanying figures showingillustrative embodiments of the invention, in which:

FIGS. 1A and 1B. Illustration of general principle for PROTAC function.(1A) Exemplary PROTACs comprise a protein targeting moiety (PTM; darklyshaded rectangle), a ubiquitin ligase binding moiety (ULM; lightlyshaded triangle), and optionally a linker moiety (L; black line)coupling or tethering the PTM to the ULM. (1B) Illustrates thefunctional use of the PROTACs as described herein. Briefly, the ULMrecognizes and binds to a specific E3 ubiquitin ligase, and the PTMbinds and recruits a target protein bringing it into close proximity tothe E3 ubiquitin ligase. Typically, the E3 ubiquitin ligase is complexedwith an E2 ubiquitin-conjugating protein, and either alone or via the E2protein catalyzes attachment of ubiquitin (dark circles) to a lysine onthe target protein via an isopeptide bond. The poly-ubiquitinatedprotein (far right) is then targeted for degration by the proteosomalmachinery of the cell.

FIGS. 2A, 2B, and 2C. (A) Chemical structure of Exemplary Compound 2.(B) Western blots of IRAK4 and IRAK1 protein degradation by ExemplaryCompound 2. (C) Percent degradation of IRAK 4 from the western blots ofFIG. 2B (percent remaining is shown). Graphs of percent degradation ofIRAK1 by Exemplary Compound 2 is not provided as no significantdegradation was observed, as is demonstrated in the blots of FIG. 2B.Exemplary Compound 2 demonstrated a Dmax of 71% and a DC50 of 9.7 nM.

FIGS. 3A, 3B, and 3C. (A) Chemical structure of exemplary compound 3.(B) Western blots of IRAK4 and IRAK1 protein degradation by ExemplaryCompound 3. (C) Percent degradation of IRAK 4 from the western blots ofFIG. 3B (percent remaining is shown). Graphs of percent degradation ofIRAK1 by Exemplary Compound 3 is not provided as no significantdegradation was observed, as is demonstrated in the blots of FIG. 3B.Exemplary Compound 3 demonstrated a Dmax of 80% and a DC50 of 23 nM.

FIGS. 4A, 4B, and 4C. (A) Chemical structure of exemplary compound 60.(B) Western blots of IRAK 4 protein degradation by Exemplary Compound60. (C) Percent degradation of IRAK4 from the western blots of FIG. 4B(percent remaining is shown). Exemplary Compound 60 demonstrated a Dmaxof 73% and a DC50 of 3.5 nM.

FIG. 5. IRAK4 degradation enzyme-linked immunosorbent assay data forExemplary Compound 2.

DETAILED DESCRIPTION

The following is a detailed description provided to aid those skilled inthe art in practicing the present invention. Those of ordinary skill inthe art may make modifications and variations in the embodimentsdescribed herein without departing from the spirit or scope of thepresent disclosure. All publications, patent applications, patents,figures and other references mentioned herein are expressly incorporatedby reference in their entirety.

Presently described are compositions and methods that relate to thesurprising and unexpected discovery that an E3 ubiquitin ligase protein(e.g., inhibitors of apoptosis proteins (IAP), a Von Hippel-Lindau E3ubiquitin ligase (VHL), a cereblon E3 ubiquitin ligase, or a mousedouble minute 2 homolog (MDM2) E3 ubiquitin ligase) ubiquitinates atarget protein once it and the target protein are placed in proximity bya bifunctional or chimeric construct that binds the E3 ubiquitin ligaseprotein and the target protein. Accordingly the present disclosureprovides such compounds and compositions comprising an E3 ubiquintinligase binding moiety (“ULM”) coupled to a protein target binding moiety(“PTM”), which result in the ubiquitination of a chosen target protein,which leads to degradation of the target protein by the proteasome (seeFIG. 1). The present disclosure also provides a library of compositionsand the use thereof.

In certain aspects, the present disclosure provides compounds whichcomprise a ligand, e.g., a small molecule ligand (i.e., having amolecular weight of below 2,000, 1,000, 500, or 200 Daltons), which iscapable of binding to a ubiquitin ligase, such as IAP, VHL, MDM2, orcereblon. The compounds also comprise a moiety that is capable ofbinding to target protein, in such a way that the target protein isplaced in proximity to the ubiquitin ligase to effect degradation(and/or inhibition) of that protein. Small molecule can mean, inaddition to the above, that the molecule is non-peptidyl, that is, it isnot generally considered a peptide, e.g., comprises fewer than 4, 3, or2 amino acids. In accordance with the present description, the PTM, ULMor PROTAC molecule can be a small molecule.

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. The terminology used in thedescription is for describing particular embodiments only and is notintended to be limiting of the invention.

Where a range of values is provided, it is understood that eachintervening value, to the tenth of the unit of the lower limit unlessthe context clearly dictates otherwise (such as in the case of a groupcontaining a number of carbon atoms in which case each carbon atomnumber falling within the range is provided), between the upper andlower limit of that range and any other stated or intervening value inthat stated range is encompassed within the invention. The upper andlower limits of these smaller ranges may independently be included inthe smaller ranges is also encompassed within the invention, subject toany specifically excluded limit in the stated range. Where the statedrange includes one or both of the limits, ranges excluding either bothof those included limits are also included in the invention.

The following terms are used to describe the present invention. Ininstances where a term is not specifically defined herein, that term isgiven an art-recognized meaning by those of ordinary skill applying thatterm in context to its use in describing the present invention.

The articles “a” and “an” as used herein and in the appended claims areused herein to refer to one or to more than one (i.e., to at least one)of the grammatical object of the article unless the context clearlyindicates otherwise. By way of example, “an element” means one elementor more than one element.

The phrase “and/or,” as used herein in the specification and in theclaims, should be understood to mean “either or both” of the elements soconjoined, i.e., elements that are conjunctively present in some casesand disjunctively present in other cases. Multiple elements listed with“and/or” should be construed in the same fashion, i.e., “one or more” ofthe elements so conjoined. Other elements may optionally be presentother than the elements specifically identified by the “and/or” clause,whether related or unrelated to those elements specifically identified.Thus, as a non-limiting example, a reference to “A and/or B”, when usedin conjunction with open-ended language such as “comprising” can refer,in one embodiment, to A only (optionally including elements other thanB); in another embodiment, to B only (optionally including elementsother than A); in yet another embodiment, to both A and B (optionallyincluding other elements); etc.

As used herein in the specification and in the claims, “or” should beunderstood to have the same meaning as “and/or” as defined above. Forexample, when separating items in a list, “or” or “and/or” shall beinterpreted as being inclusive, i.e., the inclusion of at least one, butalso including more than one, of a number or list of elements, and,optionally, additional unlisted items. Only terms clearly indicated tothe contrary, such as “only one of” or “exactly one of,” or, when usedin the claims, “consisting of,” will refer to the inclusion of exactlyone element of a number or list of elements. In general, the term “or”as used herein shall only be interpreted as indicating exclusivealternatives (i.e., “one or the other but not both”) when preceded byterms of exclusivity, such as “either,” “one of,” “only one of,” or“exactly one of.”

In the claims, as well as in the specification above, all transitionalphrases such as “comprising,” “including,” “carrying,” “having,”“containing,” “involving,” “holding,” “composed of,” and the like are tobe understood to be open-ended, i.e., to mean including but not limitedto. Only the transitional phrases “consisting of” and “consistingessentially of” shall be closed or semi-closed transitional phrases,respectively, as set forth in the United States Patent Office Manual ofPatent Examining Procedures, Section 2111.03.

As used herein in the specification and in the claims, the phrase “atleast one,” in reference to a list of one or more elements, should beunderstood to mean at least one element selected from anyone or more ofthe elements in the list of elements, but not necessarily including atleast one of each and every element specifically listed within the listof elements and not excluding any combinations of elements in the listof elements. This definition also allows that elements may optionally bepresent other than the elements specifically identified within the listof elements to which the phrase “at least one” refers, whether relatedor unrelated to those elements specifically identified. Thus, as anonlimiting example, “at least one of A and B” (or, equivalently, “atleast one of A or B,” or, equivalently “at least one of A and/or B”) canrefer, in one embodiment, to at least one, optionally including morethan one, A, with no B present (and optionally including elements otherthan B); in another embodiment, to at least one, optionally includingmore than one, B, with no A present (and optionally including elementsother than A); in yet another embodiment, to at least one, optionallyincluding more than one, A, and at least one, optionally including morethan one, B (and optionally including other elements); etc.

It should also be understood that, in certain methods described hereinthat include more than one step or act, the order of the steps or actsof the method is not necessarily limited to the order in which the stepsor acts of the method are recited unless the context indicatesotherwise.

The terms “co-administration” and “co-administering” or “combinationtherapy” refer to both concurrent administration (administration of twoor more therapeutic agents at the same time) and time variedadministration (administration of one or more therapeutic agents at atime different from that of the administration of an additionaltherapeutic agent or agents), as long as the therapeutic agents arepresent in the patient to some extent, preferably at effective amounts,at the same time. In certain preferred aspects, one or more of thepresent compounds described herein, are coadministered in combinationwith at least one additional bioactive agent, especially including ananticancer agent or an anti-inflammatory agent. In particularlypreferred aspects, the co-administration of compounds results insynergistic activity and/or therapy, including anticancer oranti-inflammatory activity.

The term “compound”, as used herein, unless otherwise indicated, refersto any specific chemical compound disclosed herein and includestautomers, regioisomers, geometric isomers, and where applicable,stereoisomers, including optical isomers (enantiomers) and otherstereoisomers (diastereomers) thereof, as well as pharmaceuticallyacceptable salts and derivatives, including prodrug and/or deuteratedforms thereof where applicable, in context. Deuterated small moleculescontemplated are those in which one or more of the hydrogen atomscontained in the drug molecule have been replaced by deuterium.

Within its use in context, the term compound generally refers to asingle compound, but also may include other compounds such asstereoisomers, regioisomers and/or optical isomers (including racemicmixtures) as well as specific enantiomers or enantiomerically enrichedmixtures of disclosed compounds. The term also refers, in context toprodrug forms of compounds which have been modified to facilitate theadministration and delivery of compounds to a site of activity. It isnoted that in describing the present compounds, numerous substituentsand variables associated with same, among others, are described. It isunderstood by those of ordinary skill that molecules which are describedherein are stable compounds as generally described hereunder. When thebond is shown, both a double bond and single bond are represented orunderstood within the context of the compound shown and well-known rulesfor valence interactions.

The term “ubiquitin ligase” refers to a family of proteins thatfacilitate the transfer of ubiquitin to a specific substrate protein,targeting the substrate protein for degradation. For example, IAP an E3ubiquitin ligase protein that alone or in combination with an E2ubiquitin-conjugating enzyme causes the attachment of ubiquitin to alysine on a target protein, and subsequently targets the specificprotein substrates for degradation by the proteasome. Thus, E3 ubiquitinligase alone or in complex with an E2 ubiquitin conjugating enzyme isresponsible for the transfer of ubiquitin to targeted proteins. Ingeneral, the ubiquitin ligase is involved in polyubiquitination suchthat a second ubiquitin is attached to the first; a third is attached tothe second, and so forth. Polyubiquitination marks proteins fordegradation by the proteasome. However, there are some ubiquitinationevents that are limited to mono-ubiquitination, in which only a singleubiquitin is added by the ubiquitin ligase to a substrate molecule.Mono-ubiquitinated proteins are not targeted to the proteasome fordegradation, but may instead be altered in their cellular location orfunction, for example, via binding other proteins that have domainscapable of binding ubiquitin. Further complicating matters, differentlysines on ubiquitin can be targeted by an E3 to make chains. The mostcommon lysine is Lys48 on the ubiquitin chain. This is the lysine usedto make polyubiquitin, which is recognized by the proteasome.

The term “patient” or “subject” is used throughout the specification todescribe an animal, preferably a human or a domesticated animal, to whomtreatment, including prophylactic treatment, with the compositionsaccording to the present disclosure is provided. For treatment of thoseinfections, conditions or disease states which are specific for aspecific animal such as a human patient, the term patient refers to thatspecific animal, including a domesticated animal such as a dog or cat ora farm animal such as a horse, cow, sheep, etc. In general, in thepresent disclosure, the term patient refers to a human patient unlessotherwise stated or implied from the context of the use of the term.

The term “effective” is used to describe an amount of a compound,composition or component which, when used within the context of itsintended use, effects an intended result. The term effective subsumesall other effective amount or effective concentration terms, which areotherwise described or used in the present application.

Compounds and Compositions

In one aspect, the description provides compounds comprising an E3ubiquitin ligase binding moiety (“ULM”) that is an IAP E3 ubiquitinligase binding moiety (an “ILM”), a cereblon E3 ubiquitin ligase bindingmoiety (a “CLM”), a Von Hippel-Lindae E3 ubiquitin ligase (VHL) bindingmoiety (VLM), and/or a mouse bould minute 2 homologue (MDM2) E3ubiquitin ligase binding moiety (MLM). In an exemplary embodiment, theULM is coupled to a target protein binding moiety (PTM) via a chemicallinker (L) according to the structure:

PTM-L-ULM  (A)

wherein L is a bond or a chemical linker group, ULM is a E3 ubiquitinligase binding moiety, and PTM is a target protein binding moiety. Thenumber and/or relative positions of the moieties in the compoundsillustrated herein is provided by way of example only. As would beunderstood by the skilled artisan, compounds described herein can besynthesized with any desired number and/or relative position of therespective functional moieties.

The terms ULM, ILM, VLM, MLM, and CLM are used in their inclusive senseunless the context indicates otherwise. For example, the term ULM isinclusive of all ULMs, including those that bind IAP (i.e., ILMs), MDM2(i.e., MLM), cereblon (i.e., CLM), and VHL (i.e., VLM). Further, theterm ILM is inclusive of all possible IAP E3 ubiquitin ligase bindingmoieties, the term MLM is inclusive of all possible MDM2 E3 ubiquiteinligase binding moieties, the term VLM is inclusive of all possible VHLbinding moieities, and the term CLM is inclusive of all cereblon bindingmoieties.

In another aspect, the present disclosure provides bifunctional ormultifunctional compounds (e.g., PROTACs) useful for regulating proteinactivity by inducing the degradation of a target protein. In certainembodiments, the compound comprises an ILM or a VLM or a CLM or a MLMcoupled, e.g., linked covalently, directly or indirectly, to a moietythat binds a target protein (i.e., a protein targeting moiety or a“PTM”). In certain embodiments, the ILM/VLM/CLM/MLM and PTM are joinedor coupled via a chemical linker (L). The ILM binds the IAP E3 ubiquitinligase, the VLM binds VHL, CLM binds the cereblon E3 ubiquitin ligase,and MLM binds the MDM2 E3 ubiquitin ligase, and the PTM recognizes atarget protein and the interaction of the respective moieties with theirtargets facilitates the degradation of the target protein by placing thetarget protein in proximity to the ubiquitin ligase protein. Anexemplary bifunctional compound can be depicted as:

PTM-ILM  (B)

PTM-CLM  (C)

PTM-VLM  (D)

PTM-MLM  (E)

In certain embodiments, the bifunctional compound further comprises achemical linker (“L”). For example, the bifunctional compound can bedepicted as:

PTM-L-ILM  (F)

PTM-L-CLM  (G)

PTM-L-VLM  (H)

PTM-L-MLM  (I)

wherein the PTM is a protein/polypeptide targeting moiety, the L is achemical linker, the ILM is a IAP E3 ubiquitin ligase binding moiety,the CLM is a cereblon E3 ubiquitin ligase binding moiety, the VLM is aVHL binding moiety, and the MLM is a MDM2 E3 ubiquitin ligase bindingmoiety.

In certain embodiments, the ULM (e.g., a ILM, a CLM, a VLM, or a MLM)shows activity or binds to the E3 ubiquitin ligase (e.g., IAP E3ubiquitin ligase, cereblon E3 ubiquitin ligase, VHL, or MDM2 E3ubiquitin ligase) with an IC₅₀ of less than about 200 μM. The IC₅₀ canbe determined according to any method known in the art, e.g., afluorescent polarization assay.

In certain additional embodiments, the bifunctional compounds describedherein demonstrate an activity with an IC₅₀ of less than about 100, 50,10, 1, 0.5, 0.1, 0.05, 0.01, 0.005, 0.001 mM, or less than about 100,50, 10, 1, 0.5, 0.1, 0.05, 0.01, 0.005, 0.001 μM, or less than about100, 50, 10, 1, 0.5, 0.1, 0.05, 0.01, 0.005, 0.001 nM, or less thanabout 100, 50, 10, 1, 0.5, 0.1, 0.05, 0.01, 0.005, 0.001 μM.

In certain embodiments, the compounds as described herein comprisemultiple PTMs (targeting the same or different protein targets),multiple ULMs, one or more ULMs (i.e., moieties that bind specificallyto multiple/different E3 ubiquitin ligase, e.g., VHL, IAP, cereblon,and/or MDM2) or a combination thereof. In any of the aspects ofembodiments described herein, the PTMs and ULMs (e.g., ILM, VLM, CLM,and/or MLM) can be coupled directly or via one or more chemical linkersor a combination thereof. In additional embodiments, where a compoundhas multiple ULMs, the ULMs can be for the same E3 ubiquintin ligase oreach respective ULM can bind specifically to a different E3 ubiquitinligase. In still further embodiments, where a compound has multiplePTMs, the PTMs can bind the same target protein or each respective PTMcan bind specifically to a different target protein.

In certain embodiments, where the compound comprises multiple ULMs, theULMs are identical. In additional embodiments, the compound comprising aplurality of ULMs (e.g., ULM, ULM′, etc.), at least one PTM coupled to aULM directly or via a chemical linker (L) or both. In certain additionalembodiments, the compound comprising a plurality of ULMs furthercomprises multiple PTMs. In still additional embodiments, the PTMs arethe same or, optionally, different. In still further embodiments,wherein the PTMs are different, the respective PTMs may bind the sameprotein target or bind specifically to a different protein target.

In certain embodiments, the compound may comprise a plurality of ULMsand/or a plurality of ULM's. In further embodiments, the compoundcomprising at least two different ULMs, a plurality of ULMs, and/or aplurality of ULM's further comprises at least one PTM coupled to a ULMor a ULM′ directly or via a chemical linker or both. In any of theembodiments described herein, a compound comprising at least twodifferent ILMs can further comprise multiple PTMs. In still additionalembodiments, the PTMs are the same or, optionally, different. In stillfurther embodiments, wherein the PTMs are different the respective PTMsmay bind the same protein target or bind specifically to a differentprotein target. In still further embodiments, the PTM itself is a ULM(or ULM′), such as an ILM, a VLM, a CLM, a MLM, an ILM′, a VLM′, a CLM′,and/or a MLM′.

In additional embodiments, the description provides the compounds asdescribed herein including their enantiomers, diastereomers, solvatesand polymorphs, including pharmaceutically acceptable salt formsthereof, e.g., acid and base salt forms.

Exemplary ILMs

AVPI Tetrapeptide Fragments

In any of the compounds described herein, the ILM can comprise analanine-valine-proline-isoleucine (AVPI) tetrapeptide fragment or anunnatural mimetic thereof. In certain embodiments, the ILM is selectedfrom the group consisting of chemical structures represented by Formulas(I), (II), (III), (IV), and (V):

wherein:

-   -   R¹ for Formulas (I), (II), (III), (IV), and (V) is selected from        H or alkyl;    -   R² for Formulas (I), (II), (III), (IV), and (V) is selected from        H or alkyl;    -   R³ for Formulas (I), (II), (III), (IV), and (V) is selected from        H, alkyl, cycloalkyl and heterocycloalkyl;    -   R⁵ and R⁶ for Formulas (I), (II), (III), (IV), and (V) are        independently selected from H, alkyl, cycloalkyl,        heterocycloalkyl, or more preferably, R⁵ and R⁶ taken together        for Formulas (I), (II), (III), (IV), and (V) form a pyrrolidine        or a piperidine ring further optionally fused to 1-2 cycloalkyl,        heterocycloalkyl, aryl or heteroaryl rings, each of which can        then be further fused to another cycloalkyl, heterocycloalkyl,        aryl or heteroaryl ring;    -   R³ and R⁵ for Formulas (I), (II), (III), (IV), and (V) taken        together can form a 5-8-membered ring further optionally fused        to 1-2 cycloalkyl, heterocycloalkyl, aryl or heteroaryl rings;    -   R⁷ for Formulas (I), (II), (III), (IV), and (V) is selected from        cycloalkyl, cycloalkylalkyl, heterocycloalkyl,        heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl or        heteroarylalkyl, each one further optionally substituted with        1-3 substituents selected from halogen, alkyl, haloalkyl,        hydroxyl, alkoxy, cyano, (hetero)cycloalkyl or (hetero)aryl, or        R⁷ is —C(O)NH—R⁴; and    -   R⁴ is selected from alkyl, cycloalkyl, heterocycloalkyl,        cycloalkylalkyl, heterocycloalkylalkyl, aryl, arylalkyl,        heteroaryl, heteroarylalkyl, further optionally substituted with        1-3 substituents as described above.

As shown above, P1, P2, P3, and P4 of Formular (II) correlate with A, V,P, and I, respectively, of the AVPI tetrapeptide fragment or anunnatural mimetic thereof. Similarly, each of Formulas (I) and (III)through (V) have portions correlating with A, V, P, and I of the AVPItetrapeptide fragment or an unnatural mimetic thereof.

In any of the compounds described herein, the ILM can have the structureof Formula (VI), which is a derivative of IAP antagonists described inWO Pub. No. 2008/014236, or an unnatural mimetic thereof:

wherein:

-   -   R₁ of Formula (VI) is, independently selected from H,        C₁-C₄-alky, C₁-C₄-alkenyl, C₁-C₄-alkynyl or C₃-C₁₀-cycloalkyl        which are unsubstituted or substituted;    -   R₂ of Formula (VI) is, independently selected from H,        C₁-C₄-alkyl, C₁-C₄-alkenyl, C₁-C₄-alkynyl or C₃-C₁₀-cycloalkyl        which are unsubstituted or substituted;    -   R₃ of Formula (VI) is, independently selected from H, —CF₃,        —C₂H₅, C₁-C₄-alkyl, C₁-C₄-alkenyl, C₁-C₄-alkynyl, —CH₂—Z or any        R₂ and R₃ together form a heterocyclic ring;    -   each Z of Formula (VI) is, independently selected from H, —OH,        F, Cl, —CH₃, —CF₃, —CH₂Cl, —CH₂F or —CH₂OH;    -   R₄ of Formula (VI) is, independently selected from C₁-C₁₆        straight or branched alkyl, C₁-C₁₆-alkenyl, C₁-C₆-alkynyl,        C₃-C₁₀-cycloalkyl, —(CH₂)₀₋₆—Z₁, —(CH₂)₀₋₆-aryl, and        —(CH₂)₀₋₆-het, wherein alkyl, cycloalkyl, and phenyl are        unsubstituted or substituted;    -   R₅ of Formula (VI) is, independently selected from H,        C₁₋₁₀-alkyl, aryl, phenyl, C₃₋₇-cycloalkyl,        —(CH₂)₁₋₆—C₃₋₇-cycloalkyl, —C₁₋₁₀-alkyl-aryl,        —(CH₂)₀₋₆—C₃₋₇-cycloalkyl-(CH₂)₀₋₆-phenyl,        —(CH₂)₀₋₄—CH[(CH₂)₁₋₄-phenyl]₂, indanyl, —C(O)—C₁₋₁₀-alkyl,        —C(O)—(CH₂)₁₋₆—C₃₋₇-cycloalkyl, —C(O)—(CH₂)₀₋₆-phenyl,        —(CH₂)₀₋₆—C(O)-phenyl, —(CH₂)₀₋₆-het, —C(O)—(CH₂)₁₋₆-het, or R₅        is selected from a residue of an amino acid, wherein the alkyl,        cycloalkyl, phenyl, and aryl substituents are unsubstituted or        substituted;    -   Z₁ of Formula (VI) is, independently selected from        —N(R₁₀)—C(O)—C₁₋₁₀-alkyl, —N(R₁₀)—C(O)—(CH₂)₀₋₆—C₃₋₇-cycloalkyl,        —N(R₁₀)—C(O)—(CH₂)₀₋₆-phenyl, —N(R₁₀)—C(O)(CH₂)₁₋₆-het,        —C(O)—N(R₁₁)(R₁₂), —C(O)—O—C₁₋₁₀-alkyl,        —C(O)—O—(CH₂)₁₋₆—C₃₋₇-cycloalkyl, —C(O)—O—(CH₂)₀₋₆-phenyl,        —C(O)—O—(CH₂)₁₋₆-het, —O—C(O)—C₁₋₁₀-alkyl,        —O—C(O)—(CH₂)₁₋₆—C₃₋₇-cycloalkyl, —O—C(O)—(CH₂)₀₋₆-phenyl,        —O—C(O)—(CH₂)₁₋₆-het, wherein alkyl, cycloalkyl, and phenyl are        unsubstituted or substituted;    -   het of Formula (VI) is, independently selected from a 5-7 member        heterocyclic ring containing 1-4 heteroatoms selected from N, O,        and S, or an 8-12 member fused ring system including at least        one 5-7 member heterocyclic ring containing 1, 2, or 3        heteroatoms selected from N, O, and S, which heterocyclic ring        or fused ring system is unsubstituted or substituted on a carbon        or nitrogen atom;    -   R₁₀ of Formula (VI) is selected from H, —CH₃, —CF₃, —CH₂OH, or        —CH₂Cl;    -   R₁₁ and R₁₂ of Formula (VI) are independently selected from H,        C₁₋₄-alkyl, C₃₋₇-cycloalkyl, —(CH₂)₁₋₆—C₃₋₇-cycloakyl,        (CH₂)₀₋₆-phenyl, wherein alkyl, cycloalkyl, and phenyl are        unsubstituted or substituted; or R₁₁ and R₁₂ together with the        nitrogen form het, and    -   U of Formula (VI) is, independently, as shown in Formula (VII):

wherein:

-   -   each n of Formula (VII) is, independently selected from 0 to 5;    -   X of Formula (VII) is selected from the group —CH and N;    -   R_(a) and R_(b), of Formula (VII) are independently selected        from the group O, S, or N atom or C₀₋₈₋alkyl wherein one or more        of the carbon atoms in the alkyl chain are optionally replaced        by a heteroatom selected from O, S, or N, and where each alkyl        is, independently, either unsubstituted or substituted;    -   R_(d) of Formula (VII) is selected from the group        Re-Q-(R)_(p)(R_(g))_(q), and Ar₁-D-Ar₂;    -   R_(c) of Formula (VII) is selected from the group H or any R_(c)        and R_(d) together form a cycloalkyl or het; where if R_(c) and        R_(d) form a cycloalkyl or het, R₅ is attached to the formed        ring at a C or N atom;    -   p and q of Formula (VII) are independently selected from 0 or 1;    -   R_(e) of Formula (VII) is selected from the group C₁₋₈-alkyl and        alkylidene, and each Re is either unsubstituted or substituted;    -   Q is selected from the group N, O, S, S(O), and S(O)₂;    -   Ar₁ and Ar₂ of Formula (VII) are independently selected from the        group of substituted or unsubstituted aryl and het;    -   R_(f) and R_(g) of Formula (VII) are independently selected from        H, —C₁₋₁₀-alkyl, C₁₋₁₀-alkylaryl, —OH, —O—C₁₋₁₀-alkyl,        —(CH₂)₀₋₆—C₃₋₇-cycloalky, —O—(CH₂)₀₋₆-aryl, phenyl, aryl,        phenyl-phenyl, —(CH₂)₁₋₆-het, —O—(CH₂)₁₋₆-het, —OR₁₃, —C(O)—R₁₃,        —C(O)—N(R₁₃)(R₁₄), —N(R₁₃)(R₁₄), —S—R₁₃, —S(O)—R₁₃, —S(O)₂—R₁₃,        —S(O)₂—NR₁₃R₁₄, —NR₁₃—S(O)₂—R₁₄, —S—C_(t-10)-alkyl,        aryl-C₁₋₄-alkyl, or het-C₁₋₄-alkyl, wherein alkyl, cycloalkyl,        het, and aryl are unsubstituted or substituted, —SO₂—C₁₋₂-alkyl,        —SO₂—C₁₋₂-alkylphenyl, —O—C₁₋₄-alkyl, or any R_(g) and R_(f)        together form a ring selected from het or aryl;    -   D of Formula (VII) is selected from the group —CO—,        —C(O)—C₁₋₇-alkylene or arylene, —CF₂—, —O—, —S(O)_(r) where r is        0-2, 1,3-dioxalane, or C₁₋₇-alkyl-OH; where alkyl, alkylene, or        arylene are unsubstituted or substituted with one or more        halogens, OH, —O—C₁₋₆-alkyl, —S—C₁₋₆-alkyl, or —CF₃; or each D        is, independently selected from N(R_(h));    -   Rh is selected from the group H, unsubstituted or substituted        C₁₋₇-alkyl, aryl, unsubstituted or substituted        —O—(C₁₋₇-cycloalkyl), —C(O)—C₁₋₁₀-alkyl, —C(O)—C₀₋₁₀-alkyl-aryl,        —C—O—C₀₁₋₁₀-alkyl, —C—O—C₀₋₁₀-alkyl-aryl, —SO₂—C₁₋₁₀-alkyl, or        —SO₂—(C₀₋₁₀-alkylaryl);    -   R₆, R₇, R₈, and R₉ of Formula (VII) are, independently, selected        from the group H, —C₁₋₁₀-alkyl, —C₁₋₁₀-alkoxy,        aryl-C₁₋₁₀-alkoxy, —OH, —O—C₁₋₁₀-alkyl,        —(CH₂)₀₋₆—C₃₋₇-cycloalkyl, —O—(CH₂)₀₋₆-aryl, phenyl,        —(CH₂)₁₋₆-het, —O—(CH₂)₁₋₆-het, —OR₁₃, —C(O)—R₁₃,        —C(O)—N(R₁₃)(R₁₄), —N(R₁₃)(R₁₄), —S—R₁₃, —S(O)—R₁₃, —S(O)₂— R₁₃,        —S(O)₂—NR₁₃R₁₄, or —NR₁₃—S(O)₂—R₁₄; wherein each alkyl,        cycloalkyl, and aryl is unsubstituted or substituted; and any        R₆, R₇, R₈, and R₉ optionally together form a ring system;    -   R₁₃ and R₁₄ of Formula (VII) are independently selected from the        group H, C₁₋₁₀-alkyl, —(CH₂)₀₋₆—C₃₋₇-cycloalkyl,        —(CH₂)₀₋₆—(CH)₀₋₁-(aryl)₁₋₂, —C(O)—C₁₋₁₀-alkyl,        —C(O)—(CH₂)₁₋₆—C₃₋₇-cycloalkyl, —C(O)—O—(CH₂)₀₋₆-aryl,        —C(O)—(CH₂)₀₋₆—O-fluorenyl, —C(O)—NH—(CH₂)₀₋₆-aryl,        —C(O)—(CH₂)₀₋₆-aryl, —C(O)—(CH₂)₀₋₆-het, —C(S)—C₁₋₁₀-alkyl,        —C(S)—(CH₂)₁₋₆—C₃₋₇-cycloalkyl, —C(S)—O—(CH₂)₀₋₆-aryl,        —C(S)—(CH₂)₀₋₆—O-fluorenyl, —C(S)—NH—(CH₂)₀₋₆-aryl,        —C(S)—(CH₂)₀₋₆-aryl, or —C(S)—(CH₂)₁₋₆-het, wherein each alkyl,        cycloalkyl, and aryl is unsubstituted or substituted: or any R₁₃        and R₁₄ together with a nitrogen atom form het;    -   wherein alkyl substituents of R₁₃ and R₁₄ of Formula (VII) are        unsubstituted or substituted and when substituted, are        substituted by one or more substituents selected from        C₁₋₁₀-alkyl, halogen, OH, —O—C₁₋₆-alkyl, —S—C₁₋₆-alkyl, and        —CF₃; and substituted phenyl or aryl of R₁₃ and R₁₄ are        substituted by one or more substituents selected from halogen,        hydroxyl, C₁₋₄-alkyl, C₁₋₄-alkoxy, nitro, —CN,        —O—C(O)—C₁₋₄-alkyl, and —C(O)—O—C₁₋₄-aryl; or a pharmaceutically        acceptable salt or hydrate thereof.

In certain embodiments, the compound further comprises an independentlyselected second ILM attached to the ILM of Formula (VI), or an unnaturalmimetic thereof, by way of at least one additional independentlyselected linker group. In an embodiment, the second ILM is a derivativeof Formula (VI), or an unnatural mimetic thereof. In a certainembodiment, the at least one additional independently selected linkergroup comprises two additional independently selected linker groupschemically linking the ILM and the second ILM. In an embodiment, the atleast one additional linker group for an ILM of the Formula (VI), or anunnatural mimetic thereof, chemically links groups selected from R₄ andR₅. For example, an ILM of Formula (VI) and a second ILM of Formula(VI), or an unnatural mimetic thereof, can be linked as shown below:

In certain embodiments, the ILM, the at least one additionalindependently selected linker group L, and the second ILM has astructure selected from the group consisting of:

which are derivatives of IAP antagonists described in WO Pub. No.2008/014236.

In any of the compounds described herein, the ILM can have the structureof Formula (VIII), which is based on the IAP ligrands described inNdubaku, C., et al. Antagonism of c-IAP and XIAP proteins is requiredfor efficient induction of cell death by small-molecule IAP antagonists,ACS Chem. Biol., 557-566, 4 (7) (2009), or an unnatural mimetic thereof:

wherein each of A1 and A2 of Formula (VIII) is independently selectedfrom optionally substituted monocyclic, fused rings, aryls andhetoroaryls; and

R of Formula (VIII) is selected from H or Me.

In a particular embodiment, the linker group L is attached to A1 ofFormula (VIII). In another embodiment, the linker group L is attached toA2 of Formula (VIII).

In a particular embodiment, the ILM is selected from the groupconsisting of

In any of the compounds described herein, the ILM can have the structureof Formula (IX), which is derived from the chemotypes cross-referencedin Mannhold, R., et al. IAP antagonists: promising candidates for cancertherapy, Drug Discov. Today, 15 (5-6), 210-9 (2010), or an unnaturalmimetic thereof:

wherein R¹ is selected from alkyl, cycloalkyl and heterocycloalkyl and,most preferably, from isopropyl, tert-butyl, cyclohexyl andtetrahydropyranyl, and R² of Formula (IX) is selected from —OPh or H.

In any of the compounds described herein, the ILM can have the structureof Formula (X), which is derived from the chemotypes cross-referenced inMannhold, R., et al. IAP antagonists: promising candidates for cancertherapy, Drug Discov. Today, 15 (5-6), 210-9 (2010), or an unnaturalmimetic thereof:

wherein:

R¹ of Formula (X) is selected from H, —CH₂OH, —CH₂CH₂OH, —CH₂NH₂,—CH₂CH₂NH₂;

X of Formula (X) is selected from S or CH₂;

R² of Formula (X) is selected from:

R³ and R⁴ of Formula (X) are independently selected from H or Me

In any of the compounds described herein, the ILM can have the structureof Formula (XI), which is derived from the chemotypes cross-referencedin Mannhold, R., et al. IAP antagonists: promising candidates for cancertherapy, Drug Discov. Today, 15 (5-6), 210-9 (2010), or an unnaturalmimetic thereof:

wherein R¹ of Formula (XI) is selected from H or Me, and R² of Formula(XI) is selected from H or

In any of the compounds described herein, the ILM can have the structureof Formula (XII), which is derived from the chemotypes cross-referencedin Mannhold, R., et al. IAP antagonists: promising candidates for cancertherapy, Drug Discov. Today, 15 (5-6), 210-9 (2010), or an unnaturalmimetic thereof:

wherein: R¹ of Formula (XII) is selected from:

R² of Formula (XII) is selected from:

In any of the compounds described herein, the IAP E3 ubiquitin ligasebinding moiety is selected from the group consisting of:

In any of the compounds described herein, the ILM can have the structureof Formula (XIII), which is based on the IAP ligands summarized inFlygare, J. A., et al. Small-molecule pan-IAP antagonists: a patentreview, Expert Opin. Ther. Pat., 20 (2), 251-67 (2010), or an unnaturalmimetic thereof:

wherein:

Z of Formula (XIII) is absent or O;

R¹ of Formula (XIII) is selected from:

R¹⁰ of

selected from H, alkyl, or aryl;

X is selected from CH2 and O; and

is a nitrogen-containing heteroaryl.

In any of the compounds described herein, the ILM can have the structureof Formula (XIV), which is based on the IAP ligands summarized inFlygare, J. A., et al. Small-molecule pan-IAP antagonists: a patentreview, Expert Opin. Ther. Pat., 20 (2), 251-67 (2010), or an unnaturalmimetic thereof:

wherein:

Z of Formula (XIV) is absent or O;

R³ and R⁴ of Formula (XIV) are independently selected from H or Me;

R¹ of Formula (XIV) is selected from:

R¹⁰ of

is selected from H, alkyl, or aryl;

X of

is selected from CH2 and O; and

is a nitrogen-containing heteraryl.

In any of the compounds described herein, the ILM is selected from thegroup consisting of:

which are derivatives of ligands disclose in US Patent Pub. No.2008/0269140 and U.S. Pat. No. 7,244,851.

In any of the compounds described herein, the ILM can have the structureof Formula (XV), which was a derivative of the IAP ligand described inWO Pub. No. 2008/128171, or an unnatural mimetic thereof:

wherein:

Z of Formula (XV) is absent or O;

R¹ of Formula (XV) is selected from:

R¹⁰ of

is selected from H, alkyl, or aryl;

X of

is selected from CH2 and O; and

is a nitrogen-containing heteraryl; and

R² of Formula (XV) selected from H, alkyl, or acyl;

In a particular embodiment, the ILM has the following structure:

In any of the compounds described herein, the ILM can have the structureof Formula (XVI), which is based on the IAP ligand described in WO Pub.No. 2006/069063, or an unnatural mimetic thereof:

wherein:

-   -   R² of Formula (XVI) is selected from alkyl, cycloalkyl and        heterocycloalkyl; more preferably, from isopropyl, tert-butyl,        cyclohexyl and tetrahydropyranyl, most preferably from        cyclohexyl;

of Formula (XVI) is a 5- or 6-membered nitrogen-containing heteroaryl;more preferably, 5-membered nitrogen-containing heteroaryl, and mostpreferably thiazole; and Ar of Formula (XVI) is an aryl or a heteroaryl.

In any of the compounds described herein, the ILM can have the structureof Formula (XVII), which is based on the IAP ligands described in Cohen,F. et al., Antogonists of inhibitors of apoptosis proteins based onthiazole amide isosteres, Bioorg. Med. Chem. Lett., 20(7), 2229-33(2010), or an unnatural mimetic thereof:

wherein:

R¹ of Formula (XVII) is selected from the group halogen (e.g. fluorine),cyano,

X of Formula (XVII) is selected from the group O or CH2.

In any of the compounds described herein, the ILM can have the structureof Formula (XVIII), which is based on the IAP ligands described inCohen, F. et al., Antogonists of inhibitors of apoptosis proteins basedon thiazole amide isosteres, Bioorg. Med. Chem. Lett., 20(7), 2229-33(2010), or an unnatural mimetic thereof:

wherein R of Formula (XVIII) is selected from alkyl, aryl, heteroaryl,arylalkyl, heteroarylalkyl or halogen (in variable substitutionposition).

In any of the compounds described herein, the ILM can have the structureof Formula (XIX), which is based on the IAP ligands described in Cohen,F. et al., Antogonists of inhibitors of apoptosis proteins based onthiazole amide isosteres, Bioorg. Med. Chem. Lett., 20(7), 2229-33(2010), or an unnatural mimetic thereof:

wherein

is a 6-member nitrogen heteroaryl.

In a certain embodiment, the ILM of the composition is selected from thegroup consisting of:

In certain embodiments, the ILM of the composition is selected from thegroup consisting of:

In any of the compounds described herein, the ILM can have the structureof Formula (XX), which is based on the IAP ligands described in WO Pub.No. 2007/101347, or an unnatural mimetic thereof:

wherein X of Formula (XX) is selected from CH₂, O, NH, or S.

In any of the compounds described herein, the ILM can have the structureof Formula (XXI), which is based on the IAP ligands described in U.S.Pat. Nos. 7,345,081 and 7,419,975, or an unnatural mimetic thereof:

wherein:

-   -   R² of Formula (XXI) is selected from:

-   -   R⁵ of Formula (XXI) is selected from:

and

-   -   W of Formula (XXI) is selected from CH or N; and    -   R⁶ of

and are independently a mono- or bicyclic fused aryl or heteroaryl.

In certain embodiments, the ILM of the compound is selected from thegroup consisting

In certain embodiments, the ILM of the compound is selected from thegroup consisting of:

which are described in WO Pub. No. 2009/060292, U.S. Pat. No. 7,517,906,WO Pub. No. 2008/134679, WO Pub. No. 2007/130626, and WO Pub. No.2008/128121.

In any of the compounds described herein, the ILM can have the structureof Formula (XXII) or (XXIII), which are derived from the IAP ligandsdescribed in WO Pub. No. 2015/006524 and Perez H L, Discovery of potentheterodimeric antagonists of inhibitor of apoptosis proteins (IAPs) withsustained antitumor activity. J. Med. Chem. 58(3), 1556-62 (2015), or anunnatural mimetic thereof:

wherein:

-   -   R¹ of Formula (XXII) or (XXIII) is optionally substituted alkyl,        optionally substituted cycloalkyl, optionally substituted        cycloalkylalkyl, optionally substituted heterocyclyl, optionally        substituted arylalkyl or optionally substituted aryl;    -   R² of Formula (XXII) or (XXIII) is optionally substituted alkyl,        optionally substituted cycloalkyl, optionally substituted        cycloalkylalkyl, optionally substituted heterocyclyl, optionally        substituted arylalkyl or optionally substituted aryl;    -   or alternatively, R¹ and R² of Formula (XXII) or (XXIII) are        independently optionally substituted thioalkyl wherein the        substituents attached to the S atom of the thioalkyl are        optionally substituted alkyl, optionally substituted branched        alkyl, optionally substituted heterocyclyl, —(CH₂)_(v)COR²⁰,        —CH₂CHR²¹COR²² or —CH₂R₂;    -   wherein:        -   v is an integer from 1-3;        -   R²⁰ and R²² of —(CH₂)_(v)COR²⁰ and —CH₂R₂ are independently            selected from OH, NR²⁴R²⁵ or OR²⁶;        -   R²¹ of —CH₂CHR²¹COR² is selected from the group NR²⁴R₂₅;        -   R²³ of —CH₂R² is selected from optionally substituted aryl            or optionally substituted heterocyclyl, where the optional            substituents include alkyl and halogen;        -   R²⁴ of NR²⁴R²⁵ is selected from hydrogen or optionally            substituted alkyl;        -   R₂₅ of NR²⁴R²⁵ is selected from hydrogen, optionally            substituted alkyl, optionally substituted branched alkyl,            optionally substituted arylalkyl, optionally substituted            heterocyclyl, —CH₂(OCH₂CH₂O)_(m)CH₃, or a polyamine chain,            such as spermine or spermidine;        -   R₂₆ of OR²⁶ is selected from optionally substituted alkyl,            wherein the optional substituents are OH, halogen or NH₂;            and    -   m is an integer from 1-8;    -   R³ and R⁴ of Formula (XXII) or (XXIII) are independently        selected from optionally substituted alkyl, optionally        substituted cycloalkyl, optionally substituted aryl, optionally        substituted arylalkyl, optionally substituted arylalkoxy,        optionally substituted heteroaryl, optionally substituted        heterocyclyl, optionally substituted heteroarylalkyl or        optionally substituted heterocycloalkyl, wherein the        substituents are alkyl, halogen or OH;    -   R⁵, R⁶, R⁷ and R⁸ of Formula (XXII) or (XXIII) are independently        selected from hydrogen, optionally substituted alkyl or        optionally substituted cycloalkyl; and    -   X is selected from a bond or a chemical linker group, and/or a        pharmaceutically acceptable salt, tautomer or stereoisomer        thereof.

In certain embodiments, X is a bond or is selected from the groupconsisting of:

wherein “*” is the point of attachment of a PTM, L or ULM, e.g., an ILM.

In any of the compounds described herein, the ILM can have the structureof Formula (XXIV) or (XXVI), which are derived from the IAP ligandsdescribed in WO Pub. No. 2015/006524 and Perez H L, Discovery of potentheterodimeric antagonists of inhibitor of apoptosis proteins (IAPs) withsustained antitumor activity. J. Med. Chem. 58(3), 1556-62 (2015), or anunnatural mimetic thereof, and the chemical linker to linker group L asshown:

wherein:R¹ of Formula (XXIV), (XXV) or (XXVI) is selected from optionallysubstituted alkyl, optionally substituted cycloalkyl, optionallysubstituted cycloalkylalkyl, optionally substituted heterocyclyl,optionally substituted arylalkyl or optionally substituted aryl;R² of Formula (XXIV), (XXV) or (XXVI) is selected from optionallysubstituted alkyl, optionally substituted cycloalkyl, optionallysubstituted cycloalkylalkyl, optionally substituted heterocyclyl,optionally substituted arylalkyl or optionally substituted aryl; oralternatively,R¹ and R² of Formula (XXIV), (XXV) or (XXVI) are independently selectedfrom optionally substituted thioalkyl wherein the substituents attachedto the S atom of the thioalkyl are optionally substituted alkyl,optionally substituted branched alkyl, optionally substitutedheterocyclyl, —(CH₂)_(v)COR²⁰, —CH₂CHR²¹COR²² or —CH₂R²³,wherein:

-   -   v is an integer from 1-3;    -   R²⁰ and R²² of —(CH₂),COR² and —CH₂R₃ are independently selected        from OH, NR²⁴R²⁵ or OR²⁶;    -   R²¹ of —CH₂CHR²¹COR² is selected from NR²⁴R²⁵;    -   R³ of —CH₂R² is selected from optionally substituted aryl or        optionally substituted heterocyclyl, wherein the optional        substituents include alkyl and halogen;    -   R²⁴ of NR²⁴R²⁵ is selected from hydrogen or optionally        substituted alkyl;    -   R²⁵ of NR²⁴R²⁵ is selected from hydrogen, optionally substituted        alkyl, optionally substituted branched alkyl, optionally        substituted arylalkyl, optionally substituted heterocyclyl,        —CH₂(OCH₂CH₂O)_(m)CH₃, or a polyamine chain, such as spermine or        spermidine;    -   R²⁶ of OR²⁶ is selected from optionally substituted alkyl,        wherein the optional substituents are OH, halogen or NH₂; and    -   m is an integer from 1-8;    -   R³ and R⁴ of Formula (XXIV), (XXV) or (XXVI) are independently        optionally substituted alkyl, optionally substituted cycloalkyl,        optionally substituted aryl, optionally substituted arylalkyl,        optionally substituted arylalkoxy, optionally substituted        heteroaryl, optionally substituted heterocyclyl, optionally        substituted heteroarylalkyl or optionally substituted        heterocycloalkyl, wherein the substituents are alkyl, halogen or        OH;    -   R⁵, R⁶, R⁷ and R⁸ of Formula (XXIV), (XXV) or (XXVI) are        independently hydrogen, optionally substituted alkyl or        optionally substituted cycloalkyl; and/or a pharmaceutically        acceptable salt, tautomer or stereoisomer thereof.

In a particular embodiment, the ILM according to Formulas (XXII) through(XXVI):

R⁷ and R⁸ are selected from the H or Me;R⁵ and R⁶ are selected from the group comprising:

R³ and R⁴ are selected from the group comprising:

In any of the compounds described herein, the ILM can have the structureof Formula (XXVII) or (XXVII), which are derived from the IAP ligandsdescribed in WO Pub. No. 2014/055461 and Kim, K S, Discovery oftetrahydroisoquinoline-based bivalent heterodimeric IAP antagonists.Bioorg. Med. Chem. Lett. 24(21), 5022-9 (2014), or an unnatural mimeticthereof:

wherein:

-   -   R³⁵ is 1-2 substituents selected from alkyl, halogen, alkoxy,        cyano and haloalkoxy;    -   R¹ of Formula (XXVII) and (XXVIII) is selected from H or an        optionally substituted alkyl, optionally substituted cycloalkyl,        optionally substituted cycloalkylalkyl, optionally substituted        heterocyclyl, optionally substituted arylalkyl or optionally        substituted aryl;    -   R² of Formula (XXVII) and (XXVIII) is selected from H or an        optionally substituted alkyl, optionally substituted cycloalkyl,        optionally substituted cycloalkylalkyl, optionally substituted        heterocyclyl, optionally substituted arylalkyl or optionally        substituted aryl; or alternatively,    -   R¹ and R² of Formula (XXVII) and (XXVIII) are independently        selected from an optionally substituted thioalkyl —CR⁶⁰R⁶¹SR⁷⁰,        wherein R⁶⁰ and R⁶¹ are selected from H or methyl, and R⁷⁰ is        selected from an optionally substituted alkyl, optionally        substituted branched alkyl, optionally substituted heterocyclyl,        —(CH₂)_(v)COR²⁰, —CH₂CHR²¹COR²² or —CH₂R₂,    -   wherein:        -   v is an integer from 1-3;        -   R²⁰ and R²² of —(CH₂)_(v)COR²⁰ and —CH₂CHR²¹COR²² are            independently selected from OH, NR²⁴R²⁵ or OR²⁶;        -   R²¹ of —CH₂CHR²¹COR²² is selected from NR²⁴R²⁵;        -   R² of —CH₂R² is selected from an optionally substituted aryl            or optionally substituted heterocyclyl, where the optional            substituents include alkyl and halogen;        -   R²⁴ of NR²⁴R²⁵ is selected from hydrogen or optionally            substituted alkyl;        -   R₂ of NR²⁴R²⁵ is selected from hydrogen, optionally            substituted alkyl, optionally substituted branched alkyl,            optionally substituted arylalkyl, optionally substituted            heterocyclyl, —CH₂CH₂(OCH₂CH₂)_(m)CH₃, or a polyamine chain            —[CH₂CH₂(CH₂)_(δ)NH]ψCH₂CH₂(CH₂)ωNH₂, such as spermine or            spermidine;        -   wherein δ=0-2, ψ=1-3, ω=0-2;        -   R²⁶ of OR²⁶ is an optionally substituted alkyl, wherein the            optional substituents are OH, halogen or NH₂; and        -   m is an integer from 1-8,        -   R³ and R⁴ of Formula (XXVII) and (XXVIII) are independently            selected from an optionally substituted alkyl, optionally            substituted cycloalkyl, optionally substituted aryl,            optionally substituted arylalkyl, optionally substituted            arylalkoxy, optionally substituted heteroaryl, optionally            substituted heterocyclyl, optionally substituted            heteroarylalkyl or optionally substituted heterocycloalkyl,            wherein the substituents are alkyl, halogen or OH;        -   R⁵, R⁶, R⁷ and R⁸ of Formula (XXVII) and (XXVIII) are            independently selected from hydrogen, optionally substituted            alkyl or optionally substituted cycloalkyl;        -   R³¹ of Formulas (XXVII) and (XXVIII) is selected from alkyl,            aryl, arylalkyl, heteroaryl or heteroarylalkyl optionally            further substituted, preferably selected form the group            consisting of:

-   -   -   X of Formulas (XXVII) and (XXVIII) is selected from            —(CR⁸¹R⁸²)_(m)—, optionally substituted heteroaryl or            heterocyclyl,

-   -   -    Z of Formulas (XXVII) is selected from C═O, —O—, —NR,            —CONH—, —NHCO—, or may be absent;        -   R⁸¹ and R⁸² of —(CR⁸¹R⁸²)_(m)— are independently selected            from hydrogen, halogen, alkyl or cycloalkyl, or R⁸¹ and R⁸²            can be taken together to form a carbocyclic ring;        -   R¹⁰ and R¹¹ of

-   -   -    are independently selected from hydrogen, halogen or alkyl;        -   R¹², R¹³, R₁₄, R¹⁵ and R¹⁶ of

-   -   -    are independently selected from hydrogen, halogen or            optionally substituted alkyl or OR¹⁷;        -   R¹⁷ is selected from hydrogen, optionally substituted alkyl            or optionally substituted cycloalkyl;        -   m and n of —(CR²¹R²²)_(m)— and

-   -   -    independently 0, 1, 2, 3, or 4;        -   o and p of

-   -   -    are independently 0, 1, 2 or 3;        -   q and t of

-   -   -    are independently 0, 1, 2, 3, or 4;        -   r of

-   -   -    is 0 or 1;

    -   and/or a pharmaceutically acceptable salt, tautomer or        stereoisomer thereof.

In any of the compounds described herein, the ILM can have the structureof Formula (XXIX), (XXX), (XXXI), or (XXXII), which are derived from theIAP ligands described in WO Pub. No. 2014/055461 and Kim, K S, Discoveryof tetrahydroisoquinoline-based bivalent heterodimeric IAP antagonists.Bioorg. Med. Chem. Lett. 24(21), 5022-9 (2014), or an unnatural mimeticthereof, and the chemical linker to linker group L as shown:

wherein:

-   -   R² of Formula (XXIX) through (XXXII) is selected from H, an        optionally substituted alkyl, optionally substituted cycloalkyl,        optionally substituted cycloalkylalkyl, optionally substituted        heterocyclyl, optionally substituted arylalkyl or optionally        substituted aryl; or alternatively;    -   R¹ and R² of Formula (XXVII) and (XXVIII) are independently        selected from H, an optionally substituted thioalkyl        —CR⁶⁰R⁶¹SR⁷⁰ wherein R⁶⁰ and R⁶¹ are selected from H or methyl,        and R⁷⁰ is an optionally substituted alkyl, optionally        substituted branched alkyl, optionally substituted heterocyclyl,        —(CH₂),COR²⁰, —CH₂CHR²¹COR²² or —CH₂R²³;    -   wherein:    -   v is an integer from 1-3;    -   R²⁰ and R²² of —(CH₂)_(v)COR²⁰ and —CH₂CHR²¹COR²² are        independently selected from OH, NR²⁴R²⁵ or OR²⁶;    -   R²¹ of —CH₂CHR²¹COR²² is selected from NR²⁴R²⁵;    -   R²³ of —CH₂R₂ is selected from an optionally substituted aryl or        optionally substituted heterocyclyl, where the optional        substituents include alkyl and halogen;    -   R²⁴ of NR²⁴R²⁵ is selected from hydrogen or optionally        substituted alkyl;    -   R²⁵ of NR²⁴R²⁵ is selected from hydrogen, optionally substituted        alkyl, optionally substituted branched alkyl, optionally        substituted arylalkyl, optionally substituted heterocyclyl,        —CH₂CH₂(OCH₂CH₂)_(m)CH₃, or a polyamine chain        [CH₂CH₂(CH₂)_(δ)NH]_(ψ)CH₂CH₂(CH₂)ω _(r)NH₂, such as spermine or        spermidine, wherein δ=0-2, ψ=1-3, ω=0-2;    -   R²⁶ of OR²⁶ is an optionally substituted alkyl, wherein the        optional substituents are OH, halogen or NH₂;    -   m is an integer from 1-8;    -   R⁶ and R⁸ of Formula (XXIX) through (XXXII) are independently        selected from hydrogen, optionally substituted alkyl or        optionally substituted cycloalkyl; and    -   R³¹ of Formulas (XXIX) through (XXXII) is selected from alkyl,        aryl, arylalkyl, heteroaryl or heteroarylalkyl optionally        further substituted, preferably selected form the group        consisting of:

In certain embodiments, the ILM of the compound is:

In any of the compounds described herein, the ILM can have the structureof Formula (XXXIII), which are derived from the IAP ligands described inWO Pub. No. 2014/074658 and WO Pub. No. 2013/071035, or an unnaturalmimetic thereof:

wherein:

-   -   R² of Formula (XXXIII) is selected from H, an optionally        substituted alkyl, optionally substituted cycloalkyl, optionally        substituted cycloalkylalkyl, optionally substituted        heterocyclyl, optionally substituted arylalkyl or optionally        substituted aryl;    -   R⁶ and R⁸ of Formula (XXXIII) are independently selected from        hydrogen, optionally substituted alkyl or optionally substituted        cycloalkyl;    -   R³² of Formula (XXXIII) is selected from (C1-C4 alkylene)-R³³        wherein R³³ is selected from hydrogen, aryl, heteroaryl or        cycloalkyl optionally further substituted;    -   X of Formula (XXXIII) is selected from:

-   -   Z and Z′ of Formula (XXXIII) are independently selected from:

-   -   -   wherein each

-   -   -    represents a point of attachment to the compound, and Z and            Z′ cannot both be

-   -   -    in any given compound;

    -   Y of Formula (XXXIII) is selected from:

wherein Z and Z′ of Formula (XXXIII) are the same and Z is

wherein each

represents a point of attachment to the compound, X is selected from:

and

-   -   Y of Formula (XXXIII) is independently selected from:

wherein:

represents a point of attachment to a —C═—O portion of the compound;

represents a point of attachment to a —NH portion of the compound;

represents a first point of attachment to Z;

represents a second point of attachment to Z;

-   -   m is an integer from 0-3;    -   n is an integer from 1-3;    -   p is an integer from 0-4; and    -   A is —C(O)R³;    -   R³ is selected from —C(O)R³ is OH, NHCN, NHSO₂R¹⁰, NHOR¹¹ or        N(R¹²)(R¹³);    -   R¹⁰ and F¹¹ of NHSO₂R¹⁰ and NHOR¹¹ are independently selected        from hydrogen, optionally substituted —C₁-C₄ alkyl, cycloalkyl,        aryl, heteroaryl, heterocyclyl or heterocycloalkyl;

R¹² and R¹³ of N(R¹²)(R¹³) are independently selected from hydrogen,—C₁-C₄ alkyl, —(C₁-C₄) alkylene)-NH—(C₁-C₄ alkyl), and —(C₁-C₄alkylene)-O—(C₁-C₄ hydroxyalkyl), or R¹² and R¹³ taken together with thenitrogen atom to which they are commonly bound to form a saturatedheterocyclyl optionally comprising one additional heteroatom selectedfrom N, O and S, and wherein the saturated heterocycle is optionallysubstituted with methyl.

In any of the compounds described herein, the ILM can have the structureof Formula (XXXIV) or (XXXV), which are derived from the IAP ligandsdescribed in WO Pub. No. 2014/047024, or an unnatural mimetic thereof:

wherein:

-   -   X of Formula (XXXIV) or (XXXV) is absent or a group selected        from —(CR¹⁰R¹¹)_(m)—, optionally substituted heteroaryl or        optionally substituted heterocyclyl,

-   -   -   Y and Z of Formula (XXXIV) or (XXXV) are independently            selected from C═O, —O—, —NR⁹—, —CONH—, —NHCO— or may be            absent;

    -   R¹ and R² of Formula (XXXIV) or (XXXV) are independently        selected from an optionally substituted alkyl, optionally        substituted cycloalkyl, optionally substituted cycloalkylalkyl,        optionally substituted arylalkyl, optionally substituted aryl,        or

    -   R¹ and R² of Formula (XXXIV) or (XXXV) are independently        selected from optionally substituted thioalkyl wherein the        substituents attached to the S atom of the thioalkyl are        optionally substituted alkyl, optionally substituted branched        alkyl, optionally substituted heterocyclyl, —(CH₂)_(v)COR²⁰,        —CH₂CHR²¹COR²² or —CH₂R₂; wherein        -   v is an integer from 1-3;        -   R²⁰ and R²² of —(CH₂),COR²⁰ and —CH₂CHR²¹COR²² are            independently selected from OH, NR²⁴R²⁵ or OR²⁶;        -   R²¹ of —CH₂CHR²¹COR²² is selected from NR²⁴R²⁵;        -   R³ of —CH₂R₂ are selected from an optionally substituted            aryl or optionally substituted heterocyclyl, where the            optional substituents include alkyl and halogen;        -   R²⁴ of NR²⁴R²⁵ is selected from hydrogen or optionally            substituted alkyl;        -   R²⁵ of NR²⁴R²⁵ is selected from hydrogen, optionally            substituted alkyl, optionally substituted branched alkyl,            optionally substituted arylalkyl, optionally substituted            heterocyclyl, —CH₂(OCH₂CH²⁰)_(m)CH₃, or a polyamine chain;        -   R²⁶ is an optionally substituted alkyl, wherein the optional            substituents are OH, halogen or NH₂;        -   m of —(CR¹⁰R¹¹)_(m)— is an integer from 1-8;        -   R³ and R⁴ of Formula (XXXIV) or (XXXV) are independently            selected from optionally substituted alkyl, optionally            substituted cycloalkyl, optionally substituted aryl,            optionally substituted arylalkyl, optionally substituted            arylalkoxy, optionally substituted heteroaryl, optionally            substituted heterocyclyl, optionally substituted            heteroarylalkyl or optionally substituted heterocycloalkyl,            wherein the substituents are alkyl, halogen or OH;

    -   R⁵, R⁶, R⁷ and R⁸ of Formula (XXXIV) or (XXXV) are independently        selected from hydrogen, optionally substituted alkyl or        optionally substituted cycloalkyl;

    -   R¹⁰ and R¹¹ of —(CR¹⁰R¹¹)_(m)— are independently selected from        hydrogen, halogen or optionally substituted alkyl;        -   R¹² and R¹³ of

-   -   -    are independently selected from hydrogen, halogen or            optionally substituted alkyl, or R¹² and R¹³ can be taken            together to form a carbocyclic ring;        -   R₁₄, R¹⁵, R¹⁶, R¹⁷ and R¹⁸ of

-   -   -    and are independently selected from hydrogen, halogen,            optionally substituted alkyl or OR¹⁹;        -   R¹⁹ of OR¹⁹ is selected from hydrogen, optionally            substituted alkyl or optionally substituted cycloalkyl;        -   m and n of —(CR¹⁰R¹¹)_(m)— are independently 0, 1, 2, 3, or            4;        -   o and p of —(CR¹⁰R¹¹)_(m)— are independently 0, 1, 2 or 3;        -   q of —(CR¹⁰R¹¹)_(m)— is 0, 1, 2, 3, or 4; r is 0 or 1;        -   t of —(CR¹⁰R¹¹)_(m)— is 1, 2, or 3; and/or a            pharmaceutically acceptable salt, tautomer or stereoisomer            thereof.

In any of the compounds described herein, the ILM can have the structureof Formula (XXXVI), which are derived from the IAP ligands described inWO Pub. No. 2014/025759, or an unnatural mimetic thereof:

where:

-   -   A of Formula (XXXVI) is selected from:

where the dotted line represents an optional double bond;

-   -   X of Formula (XXXVI) is selected from: —(CR²¹R²²)_(m)—,

-   -   Y and Z of Formula (XXXVI) are independently selected from —O—,        —NR⁶— or are absent;    -   V of Formula (XXXVI) is selected from —N— or —CH—; W of        Formula (XXXVI) is selected from —CH— or —N—;    -   R¹ of Formula (XXXVI) is selected from an optionally substituted        alkyl, optionally substituted cycloalkyl, optionally substituted        cycloalkylalkyl, optionally substituted arylalkyl or optionally        substituted aryl;    -   R³ and R⁴ of Formula (XXXVI) are independently selected from        optionally substituted alkyl, optionally substituted cycloalkyl,        optionally substituted aryl, optionally substituted heteroaryl,        optionally substituted heterocyclyl, optionally substituted        arylalkyl, optionally substituted heteroarylalkyl or optionally        substituted heterocycloalkyl;    -   R⁵, R⁶, R⁷ and R⁸ of Formula (XXIV), (XXV) or (XXVI) are        independently selected from hydrogen, optionally substituted        alkyl or optionally substituted cycloalkyl, or preferably        methyl;    -   R⁹ and R¹⁰ of

are independently selected from hydrogen, halogen or optionallysubstituted alkyl, or R⁹ and R¹⁰ can be taken together to form a ring;

are independently selected from hydrogen, halogen, optionallysubstituted alkyl or OR¹⁵;

-   -   R¹⁵ of OR¹⁵ is selected from hydrogen, optionally substituted        alkyl or optionally substituted cycloalkyl;    -   m and n of —(CR²¹R²²)_(m)— and

are independently selected from 0, 1, 2, 3, or 4;

-   -   o and p of

and are independently selected from 0, 1, 2 or 3;q of

is selected from 0, 1, 2, 3, or 4;

-   -   r of

is selected from 0 or 1, and/or or a pharmaceutically acceptable salt,tautomer or stereoisomer thereof.

In any of the compounds described herein, the ILM can have the structureof Formula (XXXVII) or (XXXVIII), which are derived from the IAP ligandsdescribed in WO Pub. No. 2014/011712, or an unnatural mimetic thereof:

where:

-   -   X of Formulas (XXXVII) and (XXXVIII) is —(CR¹⁶R¹⁷)_(m)—,

-   -   -   or absent;

    -   Y and Z of Formula (XXXVII) and (XXXVIII) are independently        selected from —O—, C═O, NR⁶ or are absent;

    -   R¹ and R² of Formula (XXXVII) and (XXXVIII) are selected from        optionally substituted alkyl, optionally substituted cycloalkyl,        optionally substituted alkylaryl or optionally substituted aryl;

    -   R³ and R⁴ of Formula (XXXVII) and (XXXVIII) are independently        selected from optionally substituted alkyl, optionally        substituted cycloalkyl, optionally substituted cycloalkylalkyl,        optionally substituted arylalkyl or optionally substituted aryl;

    -   R⁵ and R⁶ of Formula (XXXVII) and (XXXVIII) are independently        selected from optionally substituted alkyl or optionally        substituted cycloalkyl;

    -   R⁷ and R⁸ of Formula (XXXVII) and (XXXVIII) are independently        selected from hydrogen, optionally substituted alkyl or        optionally substituted cycloalkyl, or preferably methyl;

    -   R⁹ and R¹⁰ of

are independently selected from hydrogen, optionally substituted alkyl,or R⁹ and R¹⁰ may be taken together to form a ring;

-   -   R¹¹ to R₁₄ of

are independently selected from hydrogen, halogen, optionallysubstituted alkyl or OR¹⁵;

-   -   R¹⁵ of OR¹⁵ is selected from hydrogen, optionally substituted        alkyl or optionally substituted cycloalkyl;    -   R¹⁶ and R¹⁷ of —(CR¹⁶R¹⁷)_(m)— are independently selected from        hydrogen, halogen or optionally substituted alkyl;    -   R⁵⁰ and R⁵¹ of Formula (XXXVII) and (XXXVIII) are independently        selected from optionally substituted alkyl, or R₅₀ and R⁵¹ are        taken together to form a ring;    -   m and n of —(CR¹⁶R¹⁷)_(m)— and

are independently an integer from 0-4;

-   -   o and p of

are independently an integer from 0-3;

-   -   q of

is an integer from 0-4; and

-   -   r of

is an integer from 0-1;

-   -   or a pharmaceutically acceptable salt, tautomer or stereoisomer        thereof.

In an embodiment, R¹ and R² of the ILM of Formula (XXXVII) or (XXXVIII)are t-butyl and R³ and R⁴ of the ILM of Formula (XXXVII) or (XXXVIII)are tetrahydronaphtalene.

In any of the compounds described herein, the ILM can have the structureof Formula (XXXIX) or (XL), which are derived from the IAP ligandsdescribed in WO Pub. No. 2013/071039, or an unnatural mimetic thereof:

wherein:

-   -   R⁴³ and R⁴⁴ of Formulas (XXXIX) and (XL) are independently        selected from hydrogen, alkyl, aryl, arylalkyl, heteroaryl,        heteroarylalkyl, cycloalkyl, cycloalkylalkyl further optionally        substituted, and    -   R⁶ and R⁸ of Formula (XXXIX) and (XL) are independently selected        from hydrogen, optionally substituted alkyl or optionally        substituted cycloalkyl.    -   each X of Formulas (XXXIX) and (XL) is independently selected        from:

-   -   each Z of Formulas (XXXIX) and (XL) is selected from

wherein each

represents a point of attachment to the compound; and

-   -   each Y is selected from:

wherein:

represents a point of attachment to a —C═O portion of the compound;

represents a point of attachment to an amino portion of the compound;

represents a first point of attachment to Z;

represents a second point of attachment to Z; and

-   -   A is selected from —C(O)R¹ or

or a tautomeric form of any of the foregoing, wherein:

-   -   R³ of —C(O)R³ is selected from OH, NHCN, NHS0₂R¹⁰, NHOR¹¹ or        N(R¹²)(R¹³);    -   R¹⁰ and R¹¹ of NHS0₂R¹⁰ and NHOR¹¹ are independently selected        from —C₁-C₄ alkyl, cycloalkyl, aryl, heteroaryl, or        heterocycloalkyl, any of which are optionally substituted, and        hydrogen;    -   each of R¹² and R¹³ of N(R¹²)(R¹³) are independently selected        from hydrogen, —C₁-C₄ alkyl, —(C₁-C₄ alkylene)-NH—(C₁-C₄ alkyl),        benzyl, —(C₁-C₄ alkylene)-C(O)OH, —(C₁-C₄ alkylene)-C(O)CH₃,        —CH(benzyl)-COOH, —C₁-C₄ alkoxy, and —(C₁-C₄ alkylene)-O—(C₁-C₄        hydroxyalkyl); or R¹² and R¹³ of N(R¹²)(R¹³) are taken together        with the nitrogen atom to which they are commonly bound to form        a saturated heterocyclyl optionally comprising one additional        heteroatom selected from N, O and S, and wherein the saturated        heterocycle is optionally substituted with methyl.

In any of the compounds described herein, the ILM can have the structureof Formula (XLI), which are derived from the IAP ligands described in WOPub. No. 2013/071039, or an unnatural mimetic thereof:

wherein:

-   -   W¹ of Formula (XLI) is selected from O, S, N—R^(A), or        C(R^(8a))(R^(8b));    -   W² of Formula (XLI) is selected from O, S, N—R^(A), or        C(R⁸)(R⁸); provided that W¹ and W² are not both O, or both S;    -   R¹ of Formula (XLI) is selected from H, C₁-C₆alkyl,        C₃-C₆cycloalkyl, —C₁-C₆alkyl-(substituted or unsubstituted        C₃-C₆cycloalkyl), substituted or unsubstituted aryl, substituted        or unsubstituted heteroaryl, —C₁-C₆alkyl-(substituted or        unsubstituted aryl), or —C₁-C₆alkyl-(substituted or        unsubstituted heteroaryl);    -   when X¹ is selected from O, N—R^(A), S, S(O), or S(O)₂, then X²        is C(R^(2a)R^(2b));    -   or:    -   X¹ of Formula (XLI) is selected from CR^(2c)R^(2d) and X² is        CR^(2a)R^(2b), and R^(2c) and R^(2a) together form a bond;    -   or:    -   X¹ and X² of Formula (XLI) are independently selected from C and        N, and are members of a fused substituted or unsubstituted        saturated or partially saturated 3-10 membered cycloalkyl ring,        a fused substituted or unsubstituted saturated or partially        saturated 3-10 membered heterocycloalkyl ring, a fused        substituted or unsubstituted 5-10 membered aryl ring, or a fused        substituted or unsubstituted 5-10 membered heteroaryl ring;    -   or:    -   X¹ of Formula (XLI) is selected from CH₂ and X² is C═O,        C═C(R^(C))₂, or C═NR^(C); where each R^(c) is independently        selected from H, —CN, —OH, alkoxy, substituted or unsubstituted        C₁-C₆alkyl, substituted or unsubstituted C₃-C₆cycloalkyl,        substituted or unsubstituted C₂-C₅heterocycloalkyl, substituted        or unsubstituted aryl, substituted or unsubstituted heteroaryl,        —C₁-C₆alkyl-(substituted or unsubstituted C₃-C₆cycloalkyl),        —C₁-C₆alkyl-(substituted or unsubstituted        C₂-C₅heterocycloalkyl), —C₁-C₆alkyl- (substituted or        unsubstituted aryl), or —C₁-C₆alkyl-(substituted or        unsubstituted heteroaryl);    -   R^(A) of N—R^(A) is selected from H, C₁-C₆alkyl,        —C(═O)C₁-C₂alkyl, substituted or unsubstituted aryl, or        substituted or unsubstituted heteroaryl;    -   R^(2a), R^(2b), R^(2c), R^(2d) of CR^(2c)R^(2d) and        CR^(2a)R^(2b) are independently selected from H, substituted or        unsubstituted C₁-C₆alkyl, substituted or unsubstituted        C₁-C₆heteroalkyl, substituted or unsubstituted C₃-C₆cycloalkyl,        substituted or unsubstituted C₂-C₅heterocycloalkyl, substituted        or unsubstituted aryl, substituted or unsubstituted heteroaryl,        —C₁-C₆alkyl-(substituted or unsubstituted C₃-C₆cycloalkyl),        —C₁-C₆alkyl-(substituted or unsubstituted        C₂-C₅heterocycloalkyl), —C₁-C₆alkyl- (substituted or        unsubstituted aryl), —C₁-C₆alkyl-(substituted or unsubstituted        heteroaryl) and —C(═O)R^(B);    -   R^(B) of —C(═O)R^(B) is selected from substituted or        unsubstituted C₁-C₆alkyl, substituted or unsubstituted        C₃-C₆cycloalkyl, substituted or unsubstituted        C₂-C₅heterocycloalkyl, substituted or unsubstituted aryl,        substituted or unsubstituted heteroaryl,        —C₁-C₆alkyl-(substituted or unsubstituted C₃-C₆cycloalkyl),        —C₁-C₆alkyl-(substituted or unsubstituted        C₂-C₅heterocycloalkyl), —C₁-C₆alkyl- (substituted or        unsubstituted aryl), —C₁-C₆alkyl-(substituted or unsubstituted        heteroaryl), or —NR^(D)R^(E);    -   R^(D) and R^(E) of NR^(D)R^(E) are independently selected from        H, substituted or unsubstituted C₁-C₆alkyl, substituted or        unsubstituted C₃-C₆cycloalkyl, substituted or unsubstituted        C₂-C₅heterocycloalkyl, substituted or unsubstituted aryl,        substituted or unsubstituted heteroaryl, —C₁-C₆alkyl-        (substituted or unsubstituted C₃-C₆cycloalkyl),        —C₁-C₆alkyl-(substituted or unsubstituted        C₂-C₅heterocycloalkyl), —C₁-C₆alkyl-(substituted or        unsubstituted aryl), or —C₁-C₆alkyl- (substituted or        unsubstituted heteroaryl);    -   m of Formula (XLI) is selected from 0, 1 or 2;    -   —U— of Formula (XLI) is selected from —NHC(═O)—, —C(═O)NH—,        —NHS(═O)₂—, —S(═—O)₂NH—, —NHC(═O)NH—, —NH(C═O)O—, —O(C═O)NH—, or        —NHS(═—O)₂NH—;    -   R³ of Formula (XLI) is selected from C₁-C₃alkyl, or        C₁-C₃fluoroalkyl;    -   R⁴ of Formula (XLI) is selected from —NHR⁵, —N(R⁵)₂, —N+(R⁵)₃ or        —OR⁵; each R⁵ of —NHR⁵, —N(R⁵)₂, —N+(R⁵)₃ and —OR⁵ is        independently selected from H, C₁-C₃alkyl, C₁-C₃haloalkyl,        C₁-C₃heteroalkyl and —C₁-C₃alkyl-(C₃-C₅cycloalkyl);    -   or    -   R³ and R⁵ of Formula (XLI) together with the atoms to which they        are attached form a substituted or unsubstituted 5-7 membered        ring;    -   or:    -   R³ of Formula (XLI) is bonded to a nitrogen atom of U to form a        substituted or unsubstituted 5-7 membered ring;    -   R⁶ of Formula (XLI) is selected from —NHC(═O)R⁷, —C(═O)NHR⁷,        —NHS(═O)2R⁷, —S(═O)₂NHR⁷; —NHC(═O)NHR⁷, —NHS(═O)₂NHR⁷,        —(C₁-C₃alkyl)-NHC(═O)R⁷, —(C₁-C₃alkyl)-C(═O)NHR⁷,        —(C₁-C₃alkyl)-NHS(═O)2R⁷, —(C₁-C₃alkyl)-S(═O)2NHR⁷;        —(C₁-C₃alkyl)-NHC(═O)NHR⁷, —(C₁-C₃alkyl)-NHS(═O)2NHR⁷,        substituted or unsubstituted C₂-C₁₀heterocycloalkyl, or        substituted or unsubstituted heteroaryl;    -   each R⁷ of —NHC(═O)R⁷, —C(═O)NHR⁷, —NHS(═O)2R⁷, —S(═O)₂NHR⁷;        —NHC(═O)NHR⁷, —NHS(═O)₂NHR⁷, —(C₁-C₃alkyl)-NHC(═O)R⁷,        —(C₁-C₃alkyl)-C(═O)NHR⁷, —(C₁-C₃alkyl)-NHS(═O)2R⁷,        —(C₁-C₃alkyl)-S(═O)2NHR⁷; —(C₁-C₃alkyl)-NHC(═O)NHR⁷,        —(C₁-C₃alkyl)-NHS(═O)2NHR⁷ is independently selected from        C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆heteroalkyl, a substituted or        unsubstituted C3-C10cycloalkyl, a substituted or unsubstituted        C₂-C₁₀heterocycloalkyl, a substituted or unsubstituted aryl, a        substituted or unsubstituted heteroaryl,        —C₁-C₆alkyl-(substituted or unsubstituted C₃-C₁₀cycloalkyl),        —C₁-C₆alkyl-(substituted or unsubstituted        C2-C10heterocycloalkyl, —C1-C6alkyl-(substituted or        unsubstituted aryl), —C₁-C₆alkyl-(substituted or unsubstituted        heteroaryl), —(CH2)p-CH(substituted or unsubstituted aryl)2,        —(CH₂)_(p)—CH(substituted or unsubstituted heteroaryl)2,        —(CH₂)_(P)—CH(substituted or unsubstituted aryl)(substituted or        unsubstituted heteroaryl), -(substituted or unsubstituted        aryl)-(substituted or unsubstituted aryl), -(substituted or        unsubstituted aryl)-(substituted or unsubstituted heteroaryl),        -(substituted or unsubstituted heteroaryl)-(substituted or        unsubstituted aryl), or -(substituted or unsubstituted        heteroaryl)-(substituted or unsubstituted heteroaryl);    -   p of R⁷ is selected from 0, 1 or 2;    -   R^(8a), R^(8b), R^(8c), and R^(8d) of C(R^(8a))(R^(8b)) and        C(R^(8c))(R^(8d)) are independently selected from H, C₁-C₆alkyl,        C₁-C₆fluoroalkyl, C₁-C₆ alkoxy, C₁-C₆heteroalkyl, and        substituted or unsubstituted aryl;    -   or:    -   R^(8a) and R^(8d) are as defined above, and R^(8b) and R^(8c)        together form a bond;    -   or:    -   R^(8a) and R^(8d) are as defined above, and R^(8b) and R^(8c)        together with the atoms to which they are attached form a        substituted or unsubstituted fused 5-7 membered saturated, or        partially saturated carbocyclic ring or heterocyclic ring        comprising 1-3 heteroatoms selected from S, O and N, a        substituted or unsubstituted fused 5-10 membered aryl ring, or a        substituted or unsubstituted fused 5-10 membered heteroaryl ring        comprising 1-3 heteroatoms selected from S, O and N;    -   or:    -   R^(8c) and R^(8d) are as defined above, and R^(8a) and R^(8b)        together with the atoms to which they are attached form a        substituted or unsubstituted saturated, or partially saturated        3-7 membered spirocycle or heterospirocycle comprising 1-3        heteroatoms selected from S, O and N;    -   or:    -   R^(8a) and R^(8b) are as defined above, and R^(8c) and R^(8d)        together with the atoms to which they are attached form a        substituted or unsubstituted saturated, or partially saturated        3-7 membered spirocycle or heterospirocycle comprising 1-3        heteroatoms selected from S, O and N; where each substituted        alkyl, heteroalkyl, fused ring, spirocycle, heterospirocycle,        cycloalkyl, heterocycloalkyl, aryl or heteroaryl is substituted        with 1-3 R⁹; and

each R⁹ of R^(8a), R^(8b), R^(8c) and R^(8d) is independently selectedfrom halogen, —OH, —SH, (C═O), CN, C₁-C₄alkyl, C₁-C₄fluoroalkyl, C₁-C₄alkoxy, C₁-C₄ fluoroalkoxy, —NH₂, —NH(C₁-C₄alkyl), —NH(C₁-C₄alkyl)₂,—C(═O)OH, —C(=0)NH₂, —C(═O)C₁-C₃alkyl, —S(═O)₂CH₃, —NH(C₁-C₄alkyl)-OH,—NH(C₁-C₄alkyl)-O—(C—C₄alkyl), —O(C₁-C₄alkyl)-NH2;—O(C₁-C₄alkyl)-NH—(C₁-C₄alkyl), and —O(C₁-C₄alkyl)-N—(C₁-C₄alkyl)₂, ortwo R⁹ together with the atoms to which they are attached form amethylene dioxy or ethylene dioxy ring substituted or unsubstituted withhalogen, —OH, or C₁-C₃alkyl. In any of the compounds described herein,the ILM can have the structure of Formula (XLII), which are derived fromthe IAP ligands described in WO Pub. No. 2013/071039, or an unnaturalmimetic thereof:

wherein:

-   -   W¹ of Formula (XLII) is O, S, N—R^(A), or C(R^(8a))(R^(8b));    -   W² of Formula (XLII) is O, S, N—R^(A), or C(R^(8c))(R^(8d));        provided that W¹ and W² are not both O, or both S;    -   R¹ of Formula (XLII) is selected from H, C₁-C₆alkyl,        C₃-C₆cycloalkyl, —C₁-C₆alkyl-(substituted or unsubstituted        C₃-C₆cycloalkyl), substituted or unsubstituted aryl, substituted        or unsubstituted heteroaryl, —C₁-C₆alkyl-(substituted or        unsubstituted aryl), or —C₁-C₆alkyl-(substituted or        unsubstituted heteroaryl);    -   when X¹ of Formula (XLII) is N—R^(A), then X² is C═O, or        CR^(2c)R^(2d), and X³ is CR^(2a)R^(2b);    -   or:    -   when X¹ of Formula (XLII) is selected from S, S(O), or S(O)₂,        then X² is CR^(2c)R^(2d), and X³ is CR^(2a)R^(2b);    -   or:    -   when X¹ of Formula (XLII) is O, then X² is CR^(2c)R^(2d) and        N—R^(A) and X³ is CR^(2a)R^(2b);    -   or:    -   when X¹ of Formula (XLII) is CH₃, then X² is selected from O,        N—R^(A), S, S(O), or S(O)₂, and X³ is CR^(2a)R^(2b);    -   when X¹ of Formula (XLII) is CR^(2e)R^(2f) and X2 is        CR^(2c)R^(2d), and R^(2e) and R^(2c) together form a bond, and        X³ of Formula (VLII) is CR^(2a)R^(2b);    -   or:    -   X¹ and X³ of Formula (XLII) are both CH₂ and X² of        Formula (XLII) is C=0, C═C(R^(C))2, or C═NR^(C) where each R^(C)        is independently selected from H, —CN, —OH, alkoxy, substituted        or unsubstituted C1-C6alkyl, substituted or unsubstituted        C₃-C₆cycloalkyl, substituted or unsubstituted        C₂-C₅heterocycloalkyl, substituted or unsubstituted aryl,        substituted or unsubstituted heteroaryl,        —C₁-C₆alkyl-(substituted or unsubstituted C₃-C₆cycloalkyl),        —C₁₋C₆alkyl-(substituted or unsubstituted        C₂-C₅heterocycloalkyl), —C₁-C₆alkyl-(substituted or        unsubstituted aryl), or —C₁-C₆alkyl- (substituted or        unsubstituted heteroaryl);    -   or:    -   X¹ and X² of Formula (XLII) are independently selected from C        and N, and are members of a fused substituted or unsubstituted        saturated or partially saturated 3-10 membered cycloalkyl ring,        a fused substituted or unsubstituted saturated or partially        saturated 3-10 membered heterocycloalkyl ring, a fused        substituted or unsubstituted 5-10 membered aryl ring, or a fused        substituted or unsubstituted 5-10 membered heteroaryl ring, and        X³ is CR^(2a)R^(2b);    -   or:    -   X² and X³ of Formula (XLII) are independently selected from C        and N, and are members of a fused substituted or unsubstituted        saturated or partially saturated 3-10 membered cycloalkyl ring,        a fused substituted or unsubstituted saturated or partially        saturated 3-10 membered heterocycloalkyl ring, a fused        substituted or unsubstituted 5-10 membered aryl ring, or a fused        substituted or unsubstituted 5-10 membered heteroaryl ring, and        X of Formula (VLII) is CR^(2e)R^(2f);    -   R^(A) of N—R^(A) is selected from H, C₁-C₆alkyl,        —C(═O)C₁-C₂alkyl, substituted or unsubstituted aryl, or        substituted or unsubstituted heteroaryl;    -   R^(2a), R^(2b), R^(2c), R^(2d), R^(2e), and R^(2f) of        CR^(2c)R^(2d), CR^(2a)R^(2b) and CR^(2e)CR² are independently        selected from H, substituted or unsubstituted C₁-C₆alkyl,        substituted or unsubstituted C₁-C₆heteroalkyl, substituted or        unsubstituted C₃-C₆cycloalkyl, substituted or unsubstituted        C₂-C₅heterocycloalkyl, substituted or unsubstituted aryl,        substituted or unsubstituted heteroaryl,        —C₁-C₆alkyl-(substituted or unsubstituted C₃-C₆cycloalkyl),        —C₁-C₆alkyl-(substituted or unsubstituted        C₂-C₅heterocycloalkyl), —C₁-C₆alkyl-(substituted or        unsubstituted aryl), —C₁₋C₆alkyl-(substituted or unsubstituted        heteroaryl) and —C(═O)R^(B);    -   R^(B) of —C(═O)R^(B) is selected from substituted or        unsubstituted C₁-C₆alkyl, substituted or unsubstituted        C₃-C₆cycloalkyl, substituted or unsubstituted        C₂-C₅heterocycloalkyl, substituted or unsubstituted aryl,        substituted or unsubstituted heteroaryl,        —C₁-C₆alkyl-(substituted or unsubstituted C₃-C₆cycloalkyl),        —C₁-C₆alkyl-(substituted or unsubstituted        C₂-C₅heterocycloalkyl), —C₁-C₆alkyl- (substituted or        unsubstituted aryl), —C₁-C₆alkyl-(substituted or unsubstituted        heteroaryl), or —NR^(D)R^(E); R^(D) and R^(E) of NR^(D)R^(E) are        independently selected from H, substituted or unsubstituted        C₁-C₆alkyl, substituted or unsubstituted C₃-C₆cycloalkyl,        substituted or unsubstituted C₂-C₅heterocycloalkyl, substituted        or unsubstituted aryl, substituted or unsubstituted heteroaryl,        —C₁-C₆alkyl- (substituted or unsubstituted C₃-C₆cycloalkyl),        —C₁-C₆alkyl-(substituted or unsubstituted        C₂-C₅heterocycloalkyl), —C₁-C₆alkyl-(substituted or        unsubstituted aryl), or —C₁-C₆alkyl- (substituted or        unsubstituted heteroaryl);    -   m of Formula (XLII) is selected from 0, 1 or 2;    -   —U— of Formula (XLII) is selected from —NHC(═O)—, —C(═O)NH—,        —NHS(═O)₂—, —S(═O)₂NH—, —NHC(═O)NH—, —NH(C═O)O—, —O(C═O)NH—, or        —NHS(═O)₂NH—;    -   R³ of Formula (XLII) is selected from C₁-C₃alkyl, or        C₁-C₃fluoroalkyl;    -   R⁴ of Formula (XLII) is selected from —NHR⁵, —N(R⁵)₂, —N+(R⁵)₃        or —OR⁵; each R⁵ of —NHR⁵, —N(R⁵)₂, —N+(R⁵)₃ and —OR⁵ is        independently selected from H, C₁-C₃alkyl, C₁-C₃haloalkyl,        C₁-C₃heteroalkyl and —C₁-C₃alkyl-(C₃-C₅cycloalkyl);    -   or:    -   R³ and R⁵ of Formula (XLII) together with the atoms to which        they are attached form a substituted or unsubstituted 5-7        membered ring;    -   or:    -   R³ of Formula (XLII) is bonded to a nitrogen atom of U to form a        substituted or unsubstituted 5-7 membered ring;    -   R⁶ of Formula (XLII) is selected from —NHC(═O)R⁷, —C(═O)NHR⁷,        —NHS(═O)2R⁷, S(═O)₂NHR⁷; —NHC(═O)NHR⁷, —NHS(═O)₂NHR⁷,        —(C₁-C₃alkyl)-NHC(═O)R⁷, —(C₁-C₃alkyl)-C(═O)NHR⁷,        —(C₁-C₃alkyl)-NHS(═O)2R⁷, —(C₁-C₃alkyl)-S(═O)2NHR⁷;        —(C₁-C₃alkyl)-NHC(═O)NHR⁷, —(C₁-C₃alkyl)-NHS(═O)₂NHR⁷,        substituted or unsubstituted C₂-C₁₀heterocycloalkyl, or        substituted or unsubstituted heteroaryl;    -   each R⁷ of —NHC(═O)R⁷, —C(═O)NHR⁷, —NHS(═O)₂R⁷, —S(═O)₂NHR⁷;        —NHC(═O)NHR⁷, NHS(═O)₂NHR⁷, —(C₁-C₃alkyl)-NHC(═O)R⁷,        —(C₁-C₃alkyl)-C(═O)NHR⁷, —(C₁-C₃alkyl)-NHS(═O)₂R⁷,        —(C₁-C₃alkyl)-S(═O)₂NHR⁷; —(C₁-C₃alkyl)-NHC(═O)NHR⁷,        —(C₁-C₃alkyl)-NHS(═O)₂NHR⁷ is independently selected from        C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆heteroalkyl, a substituted or        unsubstituted C3-C10cycloalkyl, a substituted or unsubstituted        C₂-C₁₀heterocycloalkyl, a substituted or unsubstituted aryl, a        substituted or unsubstituted heteroaryl,        —C₁-C₆alkyl-(substituted or unsubstituted C₃-C₁₀cycloalkyl),        —C₁-C₆alkyl-(substituted or unsubstituted        C2-C10heterocycloalkyl, —C1-C6alkyl-(substituted or        unsubstituted aryl), —C₁-C₆alkyl-(substituted or unsubstituted        heteroaryl), —(CH2)p-CH(substituted or unsubstituted aryl)₂,        —(CH₂)_(p)—CH(substituted or unsubstituted heteroaryl)₂,        —(CH₂)_(P)—CH(substituted or unsubstituted aryl)(substituted or        unsubstituted heteroaryl), -(substituted or unsubstituted        aryl)-(substituted or unsubstituted aryl), -(substituted or        unsubstituted aryl)-(substituted or unsubstituted heteroaryl),        -(substituted or unsubstituted heteroaryl)-(substituted or        unsubstituted aryl), or -(substituted or unsubstituted        heteroaryl)-(substituted or unsubstituted heteroaryl);    -   p of R⁷ is selected from 0, 1 or 2;    -   R^(8a), R^(8b), R^(8c), and R^(8d) of C(R^(8a))(R^(8b)) and        C(R^(8C))(R^(8d)) are independently selected from H, C₁-C₆alkyl,        C₁-C₆fluoroalkyl, C₁-C₆ alkoxy, C₁-C₆heteroalkyl, and        substituted or unsubstituted aryl;    -   or:    -   R^(8a) and R^(8d) are as defined above, and R^(8b) and R^(8c)        together form a bond;    -   or:    -   R^(8a) and R^(8d) are as defined above, and R^(8b) and R^(8c)        together with the atoms to which they are attached form a        substituted or unsubstituted fused 5-7 membered saturated, or        partially saturated carbocyclic ring or heterocyclic ring        comprising 1-3 heteroatoms selected from S, O and N, a        substituted or unsubstituted fused 5-10 membered aryl ring, or a        substituted or unsubstituted fused 5-10 membered heteroaryl ring        comprising 1-3 heteroatoms selected from S, O and N;    -   or:    -   R^(8c) and R^(8d) are as defined above, and R^(8a) and R^(8b)        together with the atoms to which they are attached form a        substituted or unsubstituted saturated, or partially saturated        3-7 membered spirocycle or heterospirocycle comprising 1-3        heteroatoms selected from S, O and N;    -   or:    -   R^(8a) and R^(8b) are as defined above, and R^(8c) and R^(8d)        together with the atoms to which they are attached form a        substituted or unsubstituted saturated, or partially saturated        3-7 membered spirocycle or heterospirocycle comprising 1-3        heteroatoms selected from S, O and N; where each substituted        alkyl, heteroalkyl, fused ring, spirocycle, heterospirocycle,        cycloalkyl, heterocycloalkyl, aryl or heteroaryl is substituted        with 1-3 R⁹; and    -   each R⁹ of R^(8a), R^(8b), R^(8c) and R^(8d) is independently        selected from halogen, —OH, —SH, (C═O), CN, C₁-C₄alkyl,        C₁-C₄fluoroalkyl, C₁-C₄ alkoxy, C₁-C₄ fluoroalkoxy, —NH₂,        —NH(C₁-C₄alkyl), —NH(C₁-C₄alkyl)₂, —C(═O)OH, —C(═O)NH₂,        —C(═O)C₁-C₃alkyl, —S(═O)₂CH₃, —NH(C₁-C₄alkyl)-OH,        —NH(C₁-C₄alkyl)-O—(C—C₄alkyl), —O(C₁-C₄alkyl)-NH2;        —O(C₁-C₄alkyl)-NH—(C₁-C₄alkyl), and        —O(C₁-C₄alkyl)-N—(C₁-C₄alkyl)₂, or two R⁹ together with the        atoms to which they are attached form a methylene dioxy or        ethylene dioxy ring substituted or unsubstituted with halogen,        —OH, or C₁-C₃alkyl.

In any of the compounds described herein, the ILM can have the structureof Formula (XLIII), which is derived from the IAP ligands described inWO Pub. No. 2013/071039, or an unnatural mimetic thereof:

wherein:

-   -   W¹ of Formula (XLIII) is selected from O, S, N—R^(A), or        C(R^(8a))(R^(8b));    -   W² of Formula (XLIII) is selected from O, S, N—R^(A), or        C(R^(8C))(R^(8d)); provided that W¹ and W² are not both O, or        both S;    -   R¹ of Formula (XLIII) is selected from H, C₁-C₆alkyl,        C₃-C₆cycloalkyl, —C₁-C₆alkyl-(substituted or unsubstituted        C₃-C₆cycloalkyl), substituted or unsubstituted aryl, substituted        or unsubstituted heteroaryl, —C₁-C₆alkyl-(substituted or        unsubstituted aryl), or —C₁-C₆alkyl-(substituted or        unsubstituted heteroaryl);    -   when X¹ of Formula (XLIII) is selected from N—R^(A), S, S(O), or        S(O)₂, then X² of Formula (XLIII) is CR^(2c)R^(2d), and X³ of        Formula (XLIII) is CR^(2a)R^(2b);    -   or:    -   when X¹ of Formula (XLIII) is O, then X² of Formula (XLIII) is        selected from O, N—R^(A), S, S(O), or S(O)₂, and X³ of        Formula (XLIII) is CR^(2a)R^(2b);    -   or:    -   when X¹ of Formula (XLIII) is CR^(2e)R^(2f) and X² of        Formula (XLIII) is CR^(2c)R^(2d), and R^(2e) and R^(2c) together        form a bond, and X³ of Formula (XLIII) is CR^(2a)R^(2b);    -   or:    -   X¹ and X² of Formula (XLIII) are independently selected from C        and N, and are members of a fused substituted or unsubstituted        saturated or partially saturated 3-10 membered cycloalkyl ring,        a fused substituted or unsubstituted saturated or partially        saturated 3-10 membered heterocycloalkyl ring, a fused        substituted or unsubstituted 5-10 membered aryl ring, or a fused        substituted or unsubstituted 5-10 membered heteroaryl ring, and        X³ of Formula (XLIII) is CR^(2a)R^(2b);    -   or:    -   X² and X³ of Formula (XLIII) are independently selected from C        and N, and are members of a fused substituted or unsubstituted        saturated or partially saturated 3-10 membered cycloalkyl ring,        a fused substituted or unsubstituted saturated or partially        saturated 3-10 membered heterocycloalkyl ring, a fused        substituted or unsubstituted 5-10 membered aryl ring, or a fused        substituted or unsubstituted 5-10 membered heteroaryl ring, and        X¹ of Formula (VLII) is CR^(2e)R^(2f);    -   R^(A) of N—R^(A) is H, C₁-C₆alkyl, —C(═O)C₁-C₂alkyl, substituted        or unsubstituted aryl, or substituted or unsubstituted        heteroaryl;    -   R^(2a), R^(2b), R^(2c), R^(2d), R^(2e), and R^(2f) of        CR^(2c)R^(2d), CR^(2a)R^(2b) and CR^(2e)R^(2f) are independently        selected from H, substituted or unsubstituted C₁-C₆alkyl,        substituted or unsubstituted C₁-C₆heteroalkyl, substituted or        unsubstituted C₃-C₆cycloalkyl, substituted or unsubstituted        C₂-C₅heterocycloalkyl, substituted or unsubstituted aryl,        substituted or unsubstituted heteroaryl,        —C₁-C₆alkyl-(substituted or unsubstituted C₃-C₆cycloalkyl),        —C₁-C₆alkyl-(substituted or unsubstituted        C₂-C₅heterocycloalkyl), —C₁-C₆alkyl-(substituted or        unsubstituted aryl), —C₁₋C₆alkyl-(substituted or unsubstituted        heteroaryl) and —C(═O)R^(B);    -   R^(B) of —C(═O)R^(B) is substituted or unsubstituted C₁-C₆alkyl,        substituted or unsubstituted C₃-C₆cycloalkyl, substituted or        unsubstituted C₂-C₅heterocycloalkyl, substituted or        unsubstituted aryl, substituted or unsubstituted heteroaryl,        —C₁-C₆alkyl-(substituted or unsubstituted C₃-C₆cycloalkyl),        —C₁-C₆alkyl-(substituted or unsubstituted        C₂-C₅heterocycloalkyl), —C₁-C₆alkyl-(substituted or        unsubstituted aryl), —C₁-C₆alkyl-(substituted or unsubstituted        heteroaryl), or —NR^(D)R^(E);    -   R^(D) and R^(E) of NR^(D)R^(E) are independently selected from        H, substituted or unsubstituted C₁-C₆alkyl, substituted or        unsubstituted C₃-C₆cycloalkyl, substituted or unsubstituted        C₂-C₅heterocycloalkyl, substituted or unsubstituted aryl,        substituted or unsubstituted heteroaryl, —C₁-C₆alkyl-        (substituted or unsubstituted C₃-C₆cycloalkyl),        —C₁-C₆alkyl-(substituted or unsubstituted        C₂-C₅heterocycloalkyl), —C₁-C₆alkyl-(substituted or        unsubstituted aryl), or —C₁-C₆alkyl- (substituted or        unsubstituted heteroaryl);    -   m of Formula (XLIII) is 0, 1 or 2;    -   —U— of Formula (XLIII) is —NHC(═O)—, —C(═O)NH—, —NHS(═O)₂—,        —S(═O)₂NH—, —NHC(═O)NH—, —NH(C═O)O—, —O(C═O)NH—, or        —NHS(═O)₂NH—;    -   R³ of Formula (XLIII) is C₁-C₃alkyl, or C₁-C₃fluoroalkyl;    -   R⁴ of Formula (XLIII) is —NHR⁵, —N(R⁵)₂, —N+(R⁵)₃ or —OR⁵;    -   each R⁵ of —NHR⁵, —N(R⁵)₂, —N+(R⁵)₃ and —OR⁵ is independently        selected from H, C₁-C₃alkyl, C₁-C₃haloalkyl, C₁-C₃heteroalkyl        and —C₁-C₃alkyl-(C₃-C₅cycloalkyl);    -   or:    -   R³ and R⁵ of Formula (XLIII) together with the atoms to which        they are attached form a substituted or unsubstituted 5-7        membered ring;    -   or:    -   R³ of Formula (XLIII) is bonded to a nitrogen atom of U to form        a substituted or unsubstituted 5-7 membered ring;    -   R⁶ of Formula (XLIII) is selected from —NHC(═O)R⁷, —C(═O)NHR⁷,        —NHS(═O)₂R⁷, S(═O)₂NHR⁷; —NHC(═O)NHR⁷, —NHS(═O)₂NHR⁷,        —(C₁-C₃alkyl)-NHC(═O)R⁷, —(C₁-C₃alkyl)-C(═O)NHR⁷,        —(C₁-C₃alkyl)-NHS(═O)₂R⁷, —(C₁-C₃alkyl)-S(═O)₂NHR⁷;        —(C₁-C₃alkyl)-NHC(═O)NHR⁷, —(C₁-C₃alkyl)-NHS(═O)₂NHR⁷,        substituted or unsubstituted C₂-C₁₀heterocycloalkyl, or        substituted or unsubstituted heteroaryl;    -   each R⁷ of —NHC(═O)R⁷, —C(═O)NHR⁷, —NHS(═O)₂R⁷, —S(═O)₂NHR⁷;        —NHC(═O)NHR⁷, NHS(═O)₂NHR⁷, —(C₁-C₃alkyl)-NHC(═O)R⁷,        —(C₁-C₃alkyl)-C(═O)NHR⁷, —(C₁-C₃alkyl)-NHS(═O)₂R⁷,        —(C₁-C₃alkyl)-S(═O)₂NHR⁷; —(C₁-C₃alkyl)-NHC(═O)NHR⁷,        —(C₁-C₃alkyl)-NHS(═O)₂NHR⁷ is independently selected from        C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆heteroalkyl, a substituted or        unsubstituted C3-C10cycloalkyl, a substituted or unsubstituted        C₂-C₁₀heterocycloalkyl, a substituted or unsubstituted aryl, a        substituted or unsubstituted heteroaryl,        —C₁-C₆alkyl-(substituted or unsubstituted C₃-C₁₀cycloalkyl),        —C₁-C₆alkyl-(substituted or unsubstituted        C2-C10heterocycloalkyl, —C1-C6alkyl-(substituted or        unsubstituted aryl), —C₁-C₆alkyl-(substituted or unsubstituted        heteroaryl), —(CH2)p-CH(substituted or unsubstituted aryl)2,        —(CH₂)_(p)—CH(substituted or unsubstituted heteroaryl)2,        —(CH₂)_(P)—CH(substituted or unsubstituted aryl)(substituted or        unsubstituted heteroaryl), -(substituted or unsubstituted        aryl)-(substituted or unsubstituted aryl), -(substituted or        unsubstituted aryl)-(substituted or unsubstituted heteroaryl),        -(substituted or unsubstituted heteroaryl)-(substituted or        unsubstituted aryl), or -(substituted or unsubstituted        heteroaryl)-(substituted or unsubstituted heteroaryl);    -   p of R⁷ is 0, 1 or 2;    -   R^(8a), R^(8b), R^(8c), and R^(8d) of C(R^(8a))(R^(8b)) and        C(R^(8c))(R^(8d)) are independently selected from H, C₁-C₆alkyl,        C₁-C₆fluoroalkyl, C₁-C₆ alkoxy, C₁-C₆heteroalkyl, and        substituted or unsubstituted aryl;    -   or:    -   R^(8a) and R^(8d) are as defined above, and R^(8b) and R^(8c)        together form a bond;    -   or:    -   R^(8a) and R^(8d) are as defined above, and R^(8b) and R^(8c)        together with the atoms to which they are attached form a        substituted or unsubstituted fused 5-7 membered saturated, or        partially saturated carbocyclic ring or heterocyclic ring        comprising 1-3 heteroatoms selected from S, O and N, a        substituted or unsubstituted fused 5-10 membered aryl ring, or a        substituted or unsubstituted fused 5-10 membered heteroaryl ring        comprising 1-3 heteroatoms selected from S, O and N;    -   or:    -   R^(8c) and R^(8d) are as defined above, and R^(8a) and R^(8b)        together with the atoms to which they are attached form a        substituted or unsubstituted saturated, or partially saturated        3-7 membered spirocycle or heterospirocycle comprising 1-3        heteroatoms selected from S, O and N;    -   or:    -   R^(8a) and R^(8b) are as defined above, and R^(8c) and R^(8d)        together with the atoms to which they are attached form a        substituted or unsubstituted saturated, or partially saturated        3-7 membered spirocycle or heterospirocycle comprising 1-3        heteroatoms selected from S, O and N; where each substituted        alkyl, heteroalkyl, fused ring, spirocycle, heterospirocycle,        cycloalkyl, heterocycloalkyl, aryl or heteroaryl is substituted        with 1-3 R⁹; and    -   each R⁹ of R^(8a), R^(8b), R^(8c) and R^(8d) is independently        selected from halogen, —OH, —SH, (C═O), CN, C₁-C₄alkyl,        C₁-C₄fluoroalkyl, C₁-C₄ alkoxy, C₁-C₄ fluoroalkoxy, —NH₂,        —NH(C₁-C₄alkyl), —NH(C₁-C₄alkyl)₂, —C(═O)OH, —C(═O)NH₂,        —C(═O)C₁-C₃alkyl, —S(═O)₂CH₃, —NH(C₁-C₄alkyl)-OH,        —NH(C₁-C₄alkyl)-O—(C—C₄alkyl), —O(C₁-C₄alkyl)-NH2;        —O(C₁-C₄alkyl)-NH—(C₁-C₄alkyl), and        —O(C₁-C₄alkyl)-N—(C₁-C₄alkyl)₂, or two R⁹ together with the        atoms to which they are attached form a methylene dioxy or        ethylene dioxy ring substituted or unsubstituted with halogen,        —OH, or C₁-C₃alkyl.

In any of the compounds described herein, the ILM can have the structureof Formula (XLIV), which is derived from the IAP ligands described in WOPub. No. 2013/071039, or an unnatural mimetic thereof:

wherein:

-   -   W¹ of Formula (XLIV) is selected from O, S, N—R^(A), or        C(R^(8a))(R^(8b));    -   W² of Formula (XLIV) is selected from O, S, N—R^(A), or        C(R^(8C))(R^(8d)); provided that W¹ and W² are not both O, or        both S;    -   W³ of Formula (XLIV) is selected from O, S, N—R^(A), or        C(R^(8e))(R^(8f)), providing that the ring comprising W¹, W²,        and W³ does not comprise two adjacent oxygen atoms or sulfer        atoms;    -   R¹ of Formula (XLIV) is selected from H, C₁-C₆alkyl,        C₃-C₆cycloalkyl, —C₁-C₆alkyl-(substituted or unsubstituted        C₃-C₆cycloalkyl), substituted or unsubstituted aryl, substituted        or unsubstituted heteroaryl, —C₁-C₆alkyl-(substituted or        unsubstituted aryl), or —C₁-C₆alkyl-(substituted or        unsubstituted heteroaryl);    -   when X¹ of Formula (XLIV) is O, then X² of Formula (XLIV) is        selected from CR^(2c)R^(2d) and N—R^(A), and X³ of        Formula (XLIV) is CR^(2a)R^(2b);    -   or:    -   when X¹ of Formula (XLIV) is CH₂, then X² of Formula (XLIV) is        selected from O, N—R^(A), S, S(O), or S(O)₂, and X³ of        Formula (XLIV) is CR^(2a)R^(2b);    -   or:    -   when X¹ of Formula (XLIV) is CR^(2e)R^(2f) and X² of        Formula (XLIV) is CR^(2c)R^(2d), and R^(2e) and R^(2c) together        form a bond, and X³ of Formula (VLIV) is CR^(2a)R^(2b);    -   or:    -   X¹ and X³ of Formula (XLIV) are both CH₂ and X² of        Formula (XLII) is C═O, C═C(R^(C))2, or C═NR^(C) where each R^(C)        is independently selected from H, —CN, —OH, alkoxy, substituted        or unsubstituted C₁-C₆alkyl, substituted or unsubstituted        C₃-C₆cycloalkyl, substituted or unsubstituted        C₂-C₅heterocycloalkyl, substituted or unsubstituted aryl,        substituted or unsubstituted heteroaryl,        —C₁-C₆alkyl-(substituted or unsubstituted C₃-C₆cycloalkyl),        —C₁-C₆alkyl-(substituted or unsubstituted        C₂-C₅heterocycloalkyl), —C₁-C₆alkyl-(substituted or        unsubstituted aryl), or —C₁-C₆alkyl- (substituted or        unsubstituted heteroaryl);    -   or:    -   X¹ and X² of Formula (XLIV) are independently selected from C        and N, and are members of a fused substituted or unsubstituted        saturated or partially saturated 3-10 membered cycloalkyl ring,        a fused substituted or unsubstituted saturated or partially        saturated 3-10 membered heterocycloalkyl ring, a fused        substituted or unsubstituted 5-10 membered aryl ring, or a fused        substituted or unsubstituted 5-10 membered heteroaryl ring, and        X³ of Formula (XLIV) is CR^(2a)R^(2b);    -   or:    -   X² and X³ of Formula (XLIV) are independently selected from C        and N, and are members of a fused substituted or unsubstituted        saturated or partially saturated 3-10 membered cycloalkyl ring,        a fused substituted or unsubstituted saturated or partially        saturated 3-10 membered heterocycloalkyl ring, a fused        substituted or unsubstituted 5-10 membered aryl ring, or a fused        substituted or unsubstituted 5-10 membered heteroaryl ring, and        X¹ of Formula (VLIV) is CR^(2e)R^(2f);    -   R^(A) of N—R^(A) is selected from H, C₁-C₆alkyl,        —C(═O)C₁-C₂alkyl, substituted or unsubstituted aryl, or        substituted or unsubstituted heteroaryl;    -   R^(2a), R^(2b), R^(2c), R^(2d), R^(2e), and R^(2f) of        CR^(2c)R^(2d), CR^(2a)R^(2b) and CR^(2e)R^(2f) are independently        selected from H, substituted or unsubstituted C₁-C₆alkyl,        substituted or unsubstituted C₁-C₆heteroalkyl, substituted or        unsubstituted C₃-C₆cycloalkyl, substituted or unsubstituted        C₂-C₅heterocycloalkyl, substituted or unsubstituted aryl,        substituted or unsubstituted heteroaryl,        —C₁-C₆alkyl-(substituted or unsubstituted C₃-C₆cycloalkyl),        —C₁-C₆alkyl-(substituted or unsubstituted        C₂-C₅heterocycloalkyl), —C₁-C₆alkyl-(substituted or        unsubstituted aryl), —C₁-C₆alkyl-(substituted or unsubstituted        heteroaryl) and —C(═O)R^(B);    -   R^(B) of —C(═O)R^(B) is selected from substituted or        unsubstituted C₁-C₆alkyl, substituted or unsubstituted        C₃-C₆cycloalkyl, substituted or unsubstituted        C₂-C₅heterocycloalkyl, substituted or unsubstituted aryl,        substituted or unsubstituted heteroaryl,        —C₁-C₆alkyl-(substituted or unsubstituted C₃-C₆cycloalkyl),        —C₁-C₆alkyl-(substituted or unsubstituted        C₂-C₅heterocycloalkyl), —C₁-C₆alkyl- (substituted or        unsubstituted aryl), —C₁-C₆alkyl-(substituted or unsubstituted        heteroaryl), or —NR^(D)R^(E);    -   R^(D) and R^(E) of NR^(D)R^(E) are independently selected from        H, substituted or unsubstituted C₁-C₆alkyl, substituted or        unsubstituted C₃-C₆cycloalkyl, substituted or unsubstituted        C₂-C₅heterocycloalkyl, substituted or unsubstituted aryl,        substituted or unsubstituted heteroaryl, —C₁-C₆alkyl-        (substituted or unsubstituted C₃-C₆cycloalkyl),        —C₁-C₆alkyl-(substituted or unsubstituted        C₂-C₅heterocycloalkyl), —C₁-C₆alkyl-(substituted or        unsubstituted aryl), or —C₁-C₆alkyl- (substituted or        unsubstituted heteroaryl); m of Formula (XLIV) is selected from        0, 1 or 2;    -   —U— of Formula (XLIV) is selected from —NHC(═O)—, —C(═O)NH—,        —NHS(═O)₂—, —S(═O)₂NH—, —NHC(═O)NH—, —NH(C═O)O—, —O(C═O)NH—, or        —NHS(═O)₂NH—;    -   R³ of Formula (XLIV) is selected from C₁-C₃alkyl, or        C₁-C₃fluoroalkyl;    -   R⁴ of Formula (XLIV) is selected from —NHR⁵, —N(R⁵)₂, —N+(R⁵)₃        or —OR⁵;    -   each R⁵ of —NHR⁵, —N(R⁵)₂, —N+(R⁵)₃ and —OR⁵ is independently        selected from H, C₁-C₃alkyl, C₁-C₃haloalkyl, C₁-C₃heteroalkyl        and —C₁-C₃alkyl-(C₃-C₅cycloalkyl);    -   or:    -   R³ and R⁵ of Formula (XLIV) together with the atoms to which        they are attached form a substituted or unsubstituted 5-7        membered ring;    -   or:    -   R³ of Formula (XLIII) is bonded to a nitrogen atom of U to form        a substituted or unsubstituted 5-7 membered ring;    -   R⁶ of Formula (XLIII) is selected from —NHC(═O)R⁷, —C(═O)NHR⁷,        —NHS(═O)₂R⁷, S(═O)₂NHR⁷; —NHC(═O)NHR⁷, —NHS(═O)₂NHR⁷,        —(C₁-C₃alkyl)-NHC(═O)R⁷, —(C₁-C₃alkyl)-C(═O)NHR⁷,        —(C₁-C₃alkyl)-NHS(═O)₂R⁷, —(C₁-C₃alkyl)-S(═O)₂NHR⁷;        —(C₁-C₃alkyl)-NHC(═O)NHR⁷, —(C₁-C₃alkyl)-NHS(═O)₂NHR⁷,        substituted or unsubstituted C₂-C₁₀heterocycloalkyl, or        substituted or unsubstituted heteroaryl;    -   each R⁷ of —NHC(═O)R⁷, —C(═O)NHR⁷, —NHS(═O)₂R⁷, —S(═O)₂NHR⁷;        —NHC(═O)NHR⁷, NHS(═O)₂NHR⁷, —(C₁-C₃alkyl)-NHC(═O)R⁷,        —(C₁-C₃alkyl)-C(═O)NHR⁷, —(C₁-C₃alkyl)-NHS(═O)₂R⁷,        —(C₁-C₃alkyl)-S(═O)₂NHR⁷; —(C₁-C₃alkyl)-NHC(═O)NHR⁷,        —(C₁-C₃alkyl)-NHS(═O)₂NHR⁷ is independently selected from        C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆heteroalkyl, a substituted or        unsubstituted C₃-C₁₀cycloalkyl, a substituted or unsubstituted        C₂-C₁₀heterocycloalkyl, a substituted or unsubstituted aryl, a        substituted or unsubstituted heteroaryl,        —C₁-C₆alkyl-(substituted or unsubstituted C₃-C₁₀cycloalkyl),        —C₁-C₆alkyl- (substituted or unsubstituted        C₂-C₁₀heterocycloalkyl, —C₁-C₆alkyl-(substituted or        unsubstituted aryl), —C₁-C₆alkyl-(substituted or unsubstituted        heteroaryl), —(CH₂)p-CH(substituted or unsubstituted aryl)₂,        —(CH₂)_(p)—CH(substituted or unsubstituted heteroaryl)₂,        —(CH₂)_(P)—CH(substituted or unsubstituted aryl)(substituted or        unsubstituted heteroaryl), -(substituted or unsubstituted        aryl)-(substituted or unsubstituted aryl), -(substituted or        unsubstituted aryl)-(substituted or unsubstituted heteroaryl),        -(substituted or unsubstituted heteroaryl)-(substituted or        unsubstituted aryl), or -(substituted or unsubstituted        heteroaryl)-(substituted or unsubstituted heteroaryl);    -   p of R⁷ is selected from 0, 1 or 2;    -   R^(8a), R^(8b), R^(8c), R^(8d), R^(8e), and R⁸ of        C(R^(8a))(R^(8b)), C(R^(8c))(R^(8d)) and C(R^(8e))(R^(8f)) are        independently selected from H, C₁-C₆alkyl, C₁-C₆fluoroalkyl,        C₁-C₆ alkoxy, C₁-C₆heteroalkyl, and substituted or unsubstituted        aryl;    -   or:    -   R^(8a), R^(8d), R^(8e), and R^(8f) of C(R^(8a))(R^(8b)),        C(R^(8c))(R^(8d)) and C(R^(8e))(R^(8f)) are as defined above,        and R^(8b) and R^(8c) together form a bond;    -   or:    -   R^(8a), R^(8b), R^(8d), and R^(8f) of C(R^(8a))(R^(8b)),        C(R^(8c))(R^(8d)) and C(R^(8e))(R^(8f)) are as defined above,        and R^(8c) and R^(8e) together form a bond;    -   or:    -   R^(8a), R^(8d), R^(8e), and R^(8f) of C(R^(8a))(R^(8b)),        C(R^(8c))(R^(8d)) and C(R^(8e))(R^(8f)) are as defined above,        and R^(8b) and R^(8c) together with the atoms to which they are        attached form a substituted or unsubstituted fused 5-7 membered        saturated, or partially saturated carbocyclic ring or        heterocyclic ring comprising 1-3 heteroatoms selected from S, O        and N, a substituted or unsubstituted fused 5-10 membered aryl        ring, or a substituted or unsubstituted fused 5-10 membered        heteroaryl ring comprising 1-3 heteroatoms selected from S, O        and N;    -   or:    -   R^(8a), R^(8b), R^(8d), and R^(8f) of C(R^(8a))(R^(8b)),        C(R^(8c))(R^(8d)) and C(R^(8e))(R^(8f)) are as defined above,        and R^(8c) and R^(8e) together with the atoms to which they are        attached form a substituted or unsubstituted fused 5-7 membered        saturated, or partially saturated carbocyclic ring or        heterocyclic ring comprising 1-3 heteroatoms selected from S, O        and N, a substituted or unsubstituted fused 5-10 membered aryl        ring, or a substituted or unsubstituted fused 5-10 membered        heteroaryl ring comprising 1-3 heteroatoms selected from S, O        and N;    -   or:    -   R^(8e), R^(8d), R^(8e), and R^(8f) of C(R^(8c))(R^(8d)) and        C(R^(8e))(R^(8f)) are as defined above, and R^(8a) and R^(8b)        together with the atoms to which they are attached form a        substituted or unsubstituted saturated, or partially saturated        3-7 membered spirocycle or heterospirocycle comprising 1-3        heteroatoms selected from S, O and N;    -   or:    -   R^(8a), R^(8b), R^(8c), and R^(8f) of C(R^(8a))(R^(8b)) and        C(R^(8e))(R^(8f)) are as defined above, and R^(8e) and R^(8d)        together with the atoms to which they are attached form a        substituted or unsubstituted saturated, or partially saturated        3-7 membered spirocycle or heterospirocycle comprising 1-3        heteroatoms selected from S, O and N;    -   or:    -   R^(8a), R^(8b), R^(8c), and R^(8d) of C(R^(8a))(R^(8b)) and        C(R^(8c))(R^(8d)) are as defined above, and R^(8e) and R^(8f)        together with the atoms to which they are attached form a        substituted or unsubstituted saturated, or partially saturated        3-7 membered spirocycle or heterospirocycle comprising 1-3        heteroatoms selected from S, O and N;    -   or:    -   where each substituted alkyl, heteroalkyl, fused ring,        spirocycle, heterospirocycle, cycloalkyl, heterocycloalkyl, aryl        or heteroaryl is substituted with 1-3 R⁹; and    -   each R⁹ of R^(8a), R^(8b), R^(8e), R^(8d), R^(8e), and R^(8f) is        independently selected from halogen, —OH, —SH, (C═O), CN,        C₁-C₄alkyl, C₁-C₄fluoroalkyl, C₁-C₄ alkoxy, C₁-C₄ fluoroalkoxy,        —NH₂, —NH(C₁-C₄alkyl), —NH(C₁-C₄alkyl)₂, —C(═O)OH, —C(═O)NH₂,        —C(═O)C₁-C₃alkyl, —S(═O)₂CH₃, —NH(C₁-C₄alkyl)-OH,        —NH(C₁-C₄alkyl)-O—(C—C₄alkyl), —O(C₁-C₄alkyl)-NH2;        —O(C₁-C₄alkyl)-NH—(C₁-C₄alkyl), and        —O(C₁-C₄alkyl)-N—(C₁-C₄alkyl)₂, or two R⁹ together with the        atoms to which they are attached form a methylene dioxy or        ethylene dioxy ring substituted or unsubstituted with halogen,        —OH, or C₁-C₃alkyl.

In any of the compounds described herein, the ILM can have the structureof Formula (XLV), (XLVI) or (XLVII), which is derived from the IAPligands described in Vamos, M., et al., Expedient synthesis of highlypotent antagonists of inhibitor of apoptosis proteins (IAPs) with uniqueselectivity for ML-IAP, ACS Chem. Biol., 8(4), 725-32 (2013), or anunnatural mimetic thereof:

wherein:

-   -   R², R³ and R⁴ of Formula (XLV) are independently selected from H        or ME;    -   X of Formula (XLV) is independently selected from O or S; and    -   R¹ of Formula (XLV) is selected from:

In a particular embodiment, the ILM has a structure according to Formula(XLVIII):

wherein R³ and R⁴ of Formula (XLVIII) are independently selected from Hor ME;

is a 5-member heterocycle selected from:

In a particular embodiment, the

of Formula XLVIII) is

In a particular embodiment, the ILM has a structure and attached to alinker group L as shown below:

In a particular embodiment, the ILM has a structure according to Formula(XLIX), (L), or (LI):

wherein:R³ of Formula (XLIX), (L) or (LI) are independently selected from H orME;

is a 5-member heterocycle selected from:

andL of Formula (XLIX), (L) or (LI) is selected from:

In a particular embodiment, L of Formula (XLIX), (L), or (LI)

In a particular embodiment, the ILM has a structure according to Formula(LII):

In a particular embodiment, the ILM according to Formula (LII) ischemically linked to the linker group L in the area denoted with

and as shown below:

In any of the compounds described herein, the ILM can have the structureof Formula (LIII) or (LIV), which is based on the IAP ligands describedin Hennessy, E J, et al., Discovery of aminopiperidine-based Smacmimetics as IAP antagonists, Bioorg. Med. Chem. Lett., 22(4), 1960-4(2012), or an unnatural mimetic thereof:

wherein:R¹ of Formulas (LIII) and (LIV) is selected from:

R² of Formulas (LIII) and (LIV) is selected from H or Me;R³ of Formulas (LIII) and (LIV) is selected from:

X of is selected from H, halogen, methyl, methoxy, hydroxy, nitro ortrifluoromethyl.

In any of the compounds described herein, the ILM can have the structureof and be chemically linked to the linker as shown in Formula (LV) or(LVI), or an unnatural mimetic thereof:

In any of the compounds described herein, the ILM can have the structureof Formula (LVII), which is based on the IAP ligands described in Cohen,F, et al., Orally bioavailable antagonists of inhibitor of apoptosisproteins based on an azabicyclooctane scaffold, J. Med. Chem., 52(6),1723-30 (2009), or an unnatural mimetic thereof:

wherein:R¹ of Formulas (LVII) is selected from:

X of

is selected from H, fluoro, methyl or methoxy.

In a particular embodiment, the ILM is represented by the followingstructure:

In a particular embodiment, the ILM is selected from the groupconsisting of, and which the chemical link between the ILM and linkergroup L is shown:

In any of the compounds described herein, the ILM is selected from thegroup consisting of the structures below, which are based on the IAPligands described in Asano, M, et al., Design, sterioselectivesynthesis, and biological evaluation of novel tri-cyclic compounds asinhibitor of apoptosis proteins (IAP) antagonists, Bioorg. Med. Chem.,21(18): 5725-37 (2013), or an unnatural mimetic thereof:

In a particular embodiment, the ILM is selected from the groupconsisting of, and which the chemical link between the ILM and linkergroup L is shown:

In any of the compounds described herein, the ILM can have the structureof Formula (LVIII), which is based on the IAP ligands described inAsano, M, et al., Design, sterioselective synthesis, and biologicalevaluation of novel tri-cyclic compounds as inhibitor of apoptosisproteins (IAP) antagonists, Bioorg. Med. Chem., 21(18): 5725-37 (2013),or an unnatural mimetic thereof:

wherein X of Formula (LVIII) is one or two substituents independentlyselected from H, halogen or cyano.

In any of the compounds described herein, the ILM can have the structureof and be chemically linked to the linker group L as shown in Formula(LIX) or (LX), or an unnatural mimetic thereof:

wherein X of Formula (LIX) and (LX) is one or two substituentsindependently selected from H, halogen or cyano, and; and L of Formulas(LIX) and (LX) is a linker group as described herein.

In any of the compounds described herein, the ILM can have the structureof Formula (LXI), which is based on the IAP ligands described inArdecky, R J, et al., Design, sysnthesis and evaluation of inhibitor ofapoptosis (IAP) antagonists that are highly selective for the BIR2domain of XIAP, Bioorg. Med. Chem., 23(14): 4253-7 (2013), or anunnatural mimetic thereof:

wherein:

of Formula (LXI) is a natural or unnatural amino acid; andR² of Formula (LXI) is selected from:

In any of the compounds described herein, the ILM can have the structureof and be chemically linked to the linker group L as shown in Formula(LXII) or (LLXIII), or an unnatural mimetic thereof:

of Formula (LXI) is a natural or unnatural amino acid; andL of Formula (LXI) is a linker group as described herein.

In any of the compounds described herein, the ILM can have the structureselected from the group consisting of, which is based on the IAP ligandsdescribed in Wang, J, et al., Discovery of novel secondmitochondrial-derived activator of caspase mimetics as selectiveinhibitor or apoptosis protein inhibitors, J. Pharmacol. Exp. Ther.,349(2): 319-29 (2014), or an unnatural mimetic thereof:

In any of the compounds described herein, the ILM has a structureaccording to Formula (LXIX), which is based on the RAP ligands describedin Hird, A W, et al., Structure-based design and synthesis of tricyclicTAP (Inhibitors of Apoptosis Proteins) inhibitors, Bioorg. Med. Chem.Lett., 24(7): 1820-4 (2014), or an unnatural mimetic thereof:

wherein R of Formula LIX is selected from the group consisting of:

R1 of

is selected from H or Me;

R2 of

is selected from alkyl or cycloalkyl;

X of

is 1-2 substitutents independently selected from halogen, hydroxy,methoxy, nitro and trifluoromethyl

Z of

is O or NH; HET of

is mono- or fused bicyclic heteroaryl; and--- of Formula (LIX) is an optional double bond.

In a particular embodiment, the ILM of the compound has a chemicalstructure as represented by:

In a particular embodiment, the ILM of the compound has a chemicalstructure selected from the group consisting of:

The term “independently” is used herein to indicate that the variable,which is independently applied, varies independently from application toapplication.

The term “alkyl” shall mean within its context a linear, branch-chainedor cyclic fully saturated hydrocarbon radical or alkyl group, preferablya C₁-C₁₀, more preferably a C₁-C₆, alternatively a C₁-C₃ alkyl group,which may be optionally substituted. Examples of alkyl groups aremethyl, ethyl, n-butyl, sec-butyl, n-hexyl, n-heptyl, n-octyl, n-nonyl,n-decyl, isopropyl, 2-methylpropyl, cyclopropyl, cyclopropylmethyl,cyclobutyl, cyclopentyl, cyclopen-tylethyl, cyclohexylethyl andcyclohexyl, among others. In certain embodiments, the alkyl group isend-capped with a halogen group (At, Br, Cl, F, or I). In certainpreferred embodiments, compounds according to the present disclosurewhich may be used to covalently bind to dehalogenase enzymes. Thesecompounds generally contain a side chain (often linked through apolyethylene glycol group) which terminates in an alkyl group which hasa halogen substituent (often chlorine or bromine) on its distal endwhich results in covalent binding of the compound containing such amoiety to the protein.

The term “Alkenyl” refers to linear, branch-chained or cyclic C₂-C₁₀(preferably C₂-C₆) hydrocarbon radicals containing at least one C═Cbond.

The term “Alkynyl” refers to linear, branch-chained or cyclic C₂-C₁₀(preferably C₂-C₆) hydrocarbon radicals containing at least one C≡Cbond.

The term “alkylene” when used, refers to a —(CH₂)_(n)— group (n is aninteger generally from 0-6), which may be optionally substituted. Whensubstituted, the alkylene group preferably is substituted on one or moreof the methylene groups with a C₁-C₆ alkyl group (including acyclopropyl group or a t-butyl group), but may also be substituted withone or more halo groups, preferably from 1 to 3 halo groups or one ortwo hydroxyl groups, O—(C₁-C₆ alkyl) groups or amino acid sidechains asotherwise disclosed herein. In certain embodiments, an alkylene groupmay be substituted with a urethane or alkoxy group (or other group)which is further substituted with a polyethylene glycol chain (of from 1to 10, preferably 1 to 6, often 1 to 4 ethylene glycol units) to whichis substituted (preferably, but not exclusively on the distal end of thepolyethylene glycol chain) an alkyl chain substituted with a singlehalogen group, preferably a chlorine group. In still other embodiments,the alkylene (often, a methylene) group, may be substituted with anamino acid sidechain group such as a sidechain group of a natural orunnatural amino acid, for example, alanine, β-alanine, arginine,asparagine, aspartic acid, cysteine, cystine, glutamic acid, glutamine,glycine, phenylalanine, histidine, isoleucine, lysine, leucine,methionine, proline, serine, threonine, valine, tryptophan or tyrosine.

The term “unsubstituted” shall mean substituted only with hydrogenatoms. A range of carbon atoms which includes C₀ means that carbon isabsent and is replaced with H. Thus, a range of carbon atoms which isC₀-C₆ includes carbons atoms of 1, 2, 3, 4, 5 and 6 and for C₀, H standsin place of carbon.

The term “substituted” or “optionally substituted” shall meanindependently (i.e., where more than substituent occurs, eachsubstituent is independent of another substituent) one or moresubstituents (independently up to five substitutents, preferably up tothree substituents, often 1 or 2 substituents on a moiety in a compoundaccording to the present disclosure and may include substituents whichthemselves may be further substituted) at a carbon (or nitrogen)position anywhere on a molecule within context, and includes assubstituents hydroxyl, thiol, carboxyl, cyano (C≡N), nitro (NO₂),halogen (preferably, 1, 2 or 3 halogens, especially on an alkyl,especially a methyl group such as a trifluoromethyl), an alkyl group(preferably, C₁-C₁₀, more preferably, C₁-C₆), aryl (especially phenyland substituted phenyl for example benzyl or benzoyl), alkoxy group(preferably, C₁-C₆ alkyl or aryl, including phenyl and substitutedphenyl), thioether (C₁-C₆ alkyl or aryl), acyl (preferably, C₁-C₆ acyl),ester or thioester (preferably, C₁-C₆ alkyl or aryl) including alkyleneester (such that attachment is on the alkylene group, rather than at theester function which is preferably substituted with a C₁-C₆ alkyl oraryl group), preferably, C₁-C₆ alkyl or aryl, halogen (preferably, F orCl), amine (including a five- or six-membered cyclic alkylene amine,further including a C₁-C₆ alkyl amine or a C₁-C₆ dialkyl amine whichalkyl groups may be substituted with one or two hydroxyl groups) or anoptionally substituted —N(C₀-C₆ alkyl)C(O)(O—C₁-C₆ alkyl) group (whichmay be optionally substituted with a polyethylene glycol chain to whichis further bound an alkyl group containing a single halogen, preferablychlorine substituent), hydrazine, amido, which is preferably substitutedwith one or two C₁-C₆ alkyl groups (including a carboxamide which isoptionally substituted with one or two C₁-C₆ alkyl groups), alkanol(preferably, C₁-C₆ alkyl or aryl), or alkanoic acid (preferably, C₁-C₆alkyl or aryl). Substituents according to the present disclosure mayinclude, for example —SiR₁R₂R₃ groups where each of R₁ and R₂ is asotherwise described herein and R₃ is H or a C₁-C₆ alkyl group,preferably R₁, R₂, R₃ in this context is a C₁-C₃ alkyl group (includingan isopropyl or t-butyl group). Each of the above-described groups maybe linked directly to the substituted moiety or alternatively, thesubstituent may be linked to the substituted moiety (preferably in thecase of an aryl or heteraryl moiety) through an optionally substituted—(CH₂)_(m)— or alternatively an optionally substituted —(OCH₂)_(m)—,—(OCH₂CH₂)_(m)— or —(CH₂CH₂O)_(m)— group, which may be substituted withany one or more of the above-described substituents. Alkylene groups—(CH₂)_(m)— or —(CH₂)_(n)— groups or other chains such as ethyleneglycol chains, as identified above, may be substituted anywhere on thechain. Preferred substitutents on alkylene groups include halogen orC₁-C₆ (preferably C₁-C₃) alkyl groups, which may be optionallysubstituted with one or two hydroxyl groups, one or two ether groups(O—C₁-C₆ groups), up to three halo groups (preferably F), or a sideshainof an amino acid as otherwise described herein and optionallysubstituted amide (preferably carboxamide substituted as describedabove) or urethane groups (often with one or two C₀-C₆ alkylsubstitutents, which group(s) may be further substituted). In certainembodiments, the alkylene group (often a single methylene group) issubstituted with one or two optionally substituted C₁-C₆ alkyl groups,preferably C₁-C₄ alkyl group, most often methyl or O-methyl groups or asidechain of an amino acid as otherwise described herein. In the presentdisclosure, a moiety in a molecule may be optionally substituted with upto five substituents, preferably up to three substituents. Most often,in the present disclosure moieties which are substituted are substitutedwith one or two substituents.

The term “substituted” (each substituent being independent of any othersubstituent) shall also mean within its context of use C₁-C₆ alkyl,C₁-C₆ alkoxy, halogen, amido, carboxamido, sulfone, includingsulfonamide, keto, carboxy, C₁-C₆ ester (oxyester or carbonylester),C₁-C₆ keto, urethane —O—C(O)—NR₁R₂ or —N(R₁)—C(O)—O—R₁, nitro, cyano andamine (especially including a C₁-C₆ alkylene-NR₁R₂, a mono- or di-C₁-C₆alkyl substituted amines which may be optionally substituted with one ortwo hydroxyl groups). Each of these groups contain unless otherwiseindicated, within context, between 1 and 6 carbon atoms. In certainembodiments, preferred substituents will include for example, —NH—,—NHC(O)—, —O—, ═O, —(CH₂)_(m)— (here, m and n are in context, 1, 2, 3,4, 5 or 6), —S—, —S(O)—, SO₂— or —NH—C(O)—NH—, —(CH₂)_(n)OH,—(CH₂)_(n)SH, —(CH₂)_(n)COOH, C₁-C₆ alkyl, —(CH₂)_(n)O—(C₁-C₆ alkyl),—(CH₂)_(n)C(O)—(C₁-C₆ alkyl), —(CH₂)_(n)OC(O)—(C₁-C₆ alkyl),—(CH₂)_(n)C(O)O—(C₁-C₆ alkyl), —(CH₂)_(n)NHC(O)—R₁,—(CH₂)_(n)C(O)—NR₁R², —(OCH₂)_(n)OH, —(CH₂O)_(n)COOH, C₁-C₆ alkyl,—(OCH₂)_(n)O—(C₁-C₆ alkyl), —(CH₂O)_(n)C(O)—(C₁-C₆ alkyl),—(OCH₂)_(n)NHC(O)—R₁, —(CH₂O)_(n)C(O)—NR₁R₂, —S(O)₂—R_(S), —S(O)—R_(S)(R_(S) is C₁-C₆ alkyl or a —(CH₂)_(m)—NR₁R₂ group), NO₂, CN or halogen(F, Cl, Br, I, preferably F or Cl), depending on the context of the useof the substituent. R₁ and R₂ are each, within context, H or a C₁-C₆alkyl group (which may be optionally substituted with one or twohydroxyl groups or up to three halogen groups, preferably fluorine). Theterm “substituted” shall also mean, within the chemical context of thecompound defined and substituent used, an optionally substituted aryl orheteroaryl group or an optionally substituted heterocyclic group asotherwise described herein. Alkylene groups may also be substituted asotherwise disclosed herein, preferably with optionally substituted C₁-C₆alkyl groups (methyl, ethyl or hydroxymethyl or hydroxyethyl ispreferred, thus providing a chiral center), a sidechain of an amino acidgroup as otherwise described herein, an amido group as describedhereinabove, or a urethane group O—C(O)—NR₁R₂ group where R₁ and R₂ areas otherwise described herein, although numerous other groups may alsobe used as substituents. Various optionally substituted moieties may besubstituted with 3 or more substituents, preferably no more than 3substituents and preferably with 1 or 2 substituents. It is noted thatin instances where, in a compound at a particular position of themolecule substitution is required (principally, because of valency), butno substitution is indicated, then that substituent is construed orunderstood to be H, unless the context of the substitution suggestsotherwise.

The term “aryl” or “aromatic”, in context, refers to a substituted (asotherwise described herein) or unsubstituted monovalent aromatic radicalhaving a single ring (e.g., benzene, phenyl, benzyl) or condensed rings(e.g., naphthyl, anthracenyl, phenanthrenyl, etc.) and can be bound tothe compound according to the present disclosure at any available stableposition on the ring(s) or as otherwise indicated in the chemicalstructure presented. Other examples of aryl groups, in context, mayinclude heterocyclic aromatic ring systems, “heteroaryl” groups havingone or more nitrogen, oxygen, or sulfur atoms in the ring (moncyclic)such as imidazole, furyl, pyrrole, furanyl, thiene, thiazole, pyridine,pyrimidine, pyrazine, triazole, oxazole or fused ring systems such asindole, quinoline, indolizine, azaindolizine, benzofurazan, etc., amongothers, which may be optionally substituted as described above. Amongthe heteroaryl groups which may be mentioned include nitrogen-containingheteroaryl groups such as pyrrole, pyridine, pyridone, pyridazine,pyrimidine, pyrazine, pyrazole, imidazole, triazole, triazine,tetrazole, indole, isoindole, indolizine, azaindolizine, purine,indazole, quinoline, dihydroquinoline, tetrahydroquinoline,isoquinoline, dihydroisoquinoline, tetrahydroisoquinoline, quinolizine,phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline,pteridine, imidazopyridine, imidazotriazine, pyrazinopyridazine,acridine, phenanthridine, carbazole, carbazoline, pyrimidine,phenanthroline, phenacene, oxadiazole, benzimidazole, pyrrolopyridine,pyrrolopyrimidine and pyridopyrimidine; sulfur-containing aromaticheterocycles such as thiophene and benzothiophene; oxygen-containingaromatic heterocycles such as furan, pyran, cyclopentapyran, benzofuranand isobenzofuran; and aromatic heterocycles comprising 2 or more heteroatoms selected from among nitrogen, sulfur and oxygen, such as thiazole,thiadizole, isothiazole, benzoxazole, benzothiazole, benzothiadiazole,phenothiazine, isoxazole, furazan, phenoxazine, pyrazoloxazole,imidazothiazole, thienofuran, furopyrrole, pyridoxazine, furopyridine,furopyrimidine, thienopyrimidine and oxazole, among others, all of whichmay be optionally substituted.

The term “substituted aryl” refers to an aromatic carbocyclic groupcomprised of at least one aromatic ring or of multiple condensed ringsat least one of which being aromatic, wherein the ring(s) aresubstituted with one or more substituents. For example, an aryl groupcan comprise a substituent(s) selected from: —(CH₂)_(n)OH,—(CH₂)_(n)—O—(C₁-C₆)alkyl, —(CH₂)_(n)—O—(CH₂)_(n)—(C₁-C₆)alkyl,—(CH₂)_(n)—C(O)(C₀-C₆) alkyl, —(CH₂)_(n)—C(O)O(C₀-C₆)alkyl,—(CH₂)_(n)—OC(O)(C₀-C₆)alkyl, amine, mono- or di-(C₁-C₆ alkyl) aminewherein the alkyl group on the amine is optionally substituted with 1 or2 hydroxyl groups or up to three halo (preferably F, Cl) groups, OH,COOH, C₁-C₆ alkyl, preferably CH₃, CF₃, OMe, OCF₃, NO₂, or CN group(each of which may be substituted in ortho-, meta- and/or para-positionsof the phenyl ring, preferably para-), an optionally substituted phenylgroup (the phenyl group itself is preferably substituted with a linkergroup attached to a PTM group, including a ULM group), and/or at leastone of F, Cl, OH, COOH, CH₃, CF₃, OMe, OCF₃, NO₂, or CN group (inortho-, meta- and/or para-positions of the phenyl ring, preferablypara-), a naphthyl group, which may be optionally substituted, anoptionally substituted heteroaryl, preferably an optionally substitutedisoxazole including a methylsubstituted isoxazole, an optionallysubstituted oxazole including a methylsubstituted oxazole, an optionallysubstituted thiazole including a methyl substituted thiazole, anoptionally substituted isothiazole including a methyl substitutedisothiazole, an optionally substituted pyrrole including amethylsubstituted pyrrole, an optionally substituted imidazole includinga methylimidazole, an optionally substituted benzimidazole ormethoxybenzylimidazole, an optionally substituted oximidazole ormethyloximidazole, an optionally substituted diazole group, including amethyldiazole group, an optionally substituted triazole group, includinga methylsubstituted triazole group, an optionally substituted pyridinegroup, including a halo-(preferably, F) or methylsubstitutedpyridinegroup or an oxapyridine group (where the pyridine group is linked to thephenyl group by an oxygen), an optionally substituted furan, anoptionally substituted benzofuran, an optionally substituteddihydrobenzofuran, an optionally substituted indole, indolizine orazaindolizine (2, 3, or 4-azaindolizine), an optionally substitutedquinoline, and combinations thereof.

“Carboxyl” denotes the group —C(O)OR, where R is hydrogen, alkyl,substituted alkyl, aryl, substituted aryl, heteroaryl or substitutedheteroaryl, whereas these generic substituents have meanings which areidentical with definitions of the corresponding groups defined herein.

The term “heteroaryl” or “hetaryl” can mean but is in no way limited toan optionally substituted quinoline (which may be attached to thepharmacophore or substituted on any carbon atom within the quinolinering), an optionally substituted indole (including dihydroindole), anoptionally substituted indolizine, an optionally substitutedazaindolizine (2, 3 or 4-azaindolizine) an optionally substitutedbenzimidazole, benzodiazole, benzoxofuran, an optionally substitutedimidazole, an optionally substituted isoxazole, an optionallysubstituted oxazole (preferably methyl substituted), an optionallysubstituted diazole, an optionally substituted triazole, a tetrazole, anoptionally substituted benzofuran, an optionally substituted thiophene,an optionally substituted thiazole (preferably methyl and/or thiolsubstituted), an optionally substituted isothiazole, an optionallysubstituted triazole (preferably a 1,2,3-triazole substituted with amethyl group, a triisopropylsilyl group, an optionally substituted—(CH₂)_(m)—O—C₁-C₆ alkyl group or an optionally substituted—(CH₂)_(m)—C(O)—O—C₁-C₆ alkyl group), an optionally substituted pyridine(2-, 3, or 4-pyridine) or a group according to the chemical structure:

wherein

-   S^(c) is CHR^(SS), NR^(URE), or O;-   R^(HET) is H, CN, NO₂, halo (preferably Cl or F), optionally    substituted C₁-C₆ alkyl (preferably substituted with one or two    hydroxyl groups or up to three halo groups (e.g. CF₃), optionally    substituted O(C₁-C₆ alkyl) (preferably substituted with one or two    hydroxyl groups or up to three halo groups) or an optionally    substituted acetylenic group —C≡C—R_(a) where R_(a) is H or a C₁-C₆    alkyl group (preferably C₁-C₃ alkyl);-   R^(SS) is H, CN, NO₂, halo (preferably F or Cl), optionally    substituted C₁-C₆ alkyl (preferably substituted with one or two    hydroxyl groups or up to three halo groups), optionally substituted    O—(C₁-C₆ alkyl) (preferably substituted with one or two hydroxyl    groups or up to three halo groups) or an optionally substituted    —C(O)(C₁-C₆ alkyl) (preferably substituted with one or two hydroxyl    groups or up to three halo groups);-   R^(URE) is H, a C₁-C₆ alkyl (preferably H or C₁-C₃ alkyl) or a    —C(O)(C₁-C₆ alkyl), each of which groups is optionally substituted    with one or two hydroxyl groups or up to three halogen, preferably    fluorine groups, or an optionally substituted heterocycle, for    example piperidine, morpholine, pyrrolidine, tetrahydrofuran,    tetrahydrothiophene, piperidine, piperazine, each of which is    optionally substituted, and-   Y^(C) is N or C—R^(YC), where R^(YC) is H, OH, CN, NO₂, halo    (preferably Cl or F), optionally substituted C₁-C₆ alkyl (preferably    substituted with one or two hydroxyl groups or up to three halo    groups (e.g. CF₃), optionally substituted O(C₁-C₆ alkyl) (preferably    substituted with one or two hydroxyl groups or up to three halo    groups) or an optionally substituted acetylenic group —C≡C—R_(a)    where R_(a) is H or a C₁-C₆ alkyl group (preferably C₁-C₃ alkyl).

The terms “aralkyl” and “heteroarylalkyl” refer to groups that compriseboth aryl or, respectively, heteroaryl as well as alkyl and/orheteroalkyl and/or carbocyclic and/or heterocycloalkyl ring systemsaccording to the above definitions.

The term “arylalkyl” as used herein refers to an aryl group as definedabove appended to an alkyl group defined above. The arylalkyl group isattached to the parent moiety through an alkyl group wherein the alkylgroup is one to six carbon atoms. The aryl group in the arylalkyl groupmay be substituted as defined above.

The term “Heterocycle” refers to a cyclic group which contains at leastone heteroatom, e.g., N, O or S, and may be aromatic (heteroaryl) ornon-aromatic. Thus, the heteroaryl moieties are subsumed under thedefinition of heterocycle, depending on the context of its use.Exemplary heteroaryl groups are described hereinabove.

Exemplary heterocyclics include: azetidinyl, benzimidazolyl,1,4-benzodioxanyl, 1,3-benzodioxolyl, benzoxazolyl, benzothiazolyl,benzothienyl, dihydroimidazolyl, dihydropyranyl, dihydrofuranyl,dioxanyl, dioxolanyl, ethyleneurea, 1,3-dioxolane, 1,3-dioxane,1,4-dioxane, furyl, homopiperidinyl, imidazolyl, imidazolinyl,imidazolidinyl, indolinyl, indolyl, isoquinolinyl, isothiazolidinyl,isothiazolyl, isoxazolidinyl, isoxazolyl, morpholinyl, naphthyridinyl,oxazolidinyl, oxazolyl, pyridone, 2-pyrrolidone, pyridine, piperazinyl,N-methylpiperazinyl, piperidinyl, phthalimide, succinimide, pyrazinyl,pyrazolinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl,quinolinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydroquinoline,thiazolidinyl, thiazolyl, thienyl, tetrahydrothiophene, oxane, oxetanyl,oxathiolanyl, thiane among others.

Heterocyclic groups can be optionally substituted with a member selectedfrom the group consisting of alkoxy, substituted alkoxy, cycloalkyl,substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl,acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy,oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxy,carboxyalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol,thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl,heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino,nitro, —SO-alkyl, —SO-substituted alkyl, —SOaryl, —SO— heteroaryl,—SO2-alkyl, —SO2-substituted alkyl, —SO2-aryl, oxo (═O), and—SO2-heteroaryl. Such heterocyclic groups can have a single ring ormultiple condensed rings. Examples of nitrogen heterocycles andheteroaryls include, but are not limited to, pyrrole, imidazole,pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine,isoindole, indole, indazole, purine, quinolizine, isoquinoline,quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline,cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine,phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine,phenothiazine, imidazolidine, imidazoline, piperidine, piperazine,indoline, morpholino, piperidinyl, tetrahydrofuranyl, and the like aswell as N-alkoxy-nitrogen containing heterocycles. The term“heterocyclic” also includes bicyclic groups in which any of theheterocyclic rings is fused to a benzene ring or a cyclohexane ring oranother heterocyclic ring (for example, indolyl, quinolyl, isoquinolyl,tetrahydroquinolyl, and the like).

The term “cycloalkyl” can mean but is in no way limited to univalentgroups derived from monocyclic or polycyclic alkyl groups orcycloalkanes, as defined herein, e.g., saturated monocyclic hydrocarbongroups having from three to twenty carbon atoms in the ring, including,but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl and the like. The term “substituted cycloalkyl” can mean butis in no way limited to a monocyclic or polycyclic alkyl group and beingsubstituted by one or more substituents, for example, amino, halogen,alkyl, substituted alkyl, carbyloxy, carbylmercapto, aryl, nitro,mercapto or sulfo, whereas these generic substituent groups havemeanings which are identical with definitions of the correspondinggroups as defined in this legend.

“Heterocycloalkyl” refers to a monocyclic or polycyclic alkyl group inwhich at least one ring carbon atom of its cyclic structure beingreplaced with a heteroatom selected from the group consisting of N, O, Sor P. “Substituted heterocycloalkyl” refers to a monocyclic orpolycyclic alkyl group in which at least one ring carbon atom of itscyclic structure being replaced with a heteroatom selected from thegroup consisting of N, O, S or P and the group is containing one or moresubstituents selected from the group consisting of halogen, alkyl,substituted alkyl, carbyloxy, carbylmercapto, aryl, nitro, mercapto orsulfo, whereas these generic substituent group have meanings which areidentical with definitions of the corresponding groups as defined inthis legend.

The term “hydrocarbyl” shall mean a compound which contains carbon andhydrogen and which may be fully saturated, partially unsaturated oraromatic and includes aryl groups, alkyl groups, alkenyl groups andalkynyl groups.

The term “independently” is used herein to indicate that the variable,which is independently applied, varies independently from application toapplication.

The term “alkyl” shall mean within its context a linear, branch-chainedor cyclic fully saturated hydrocarbon radical or alkyl group, preferablya C₁-C₁₀, more preferably a C₁-C₆, alternatively a C₁-C₃ alkyl group,which may be optionally substituted. Examples of alkyl groups aremethyl, ethyl, n-butyl, sec-butyl, n-hexyl, n-heptyl, n-octyl, n-nonyl,n-decyl, isopropyl, 2-methylpropyl, cyclopropyl, cyclopropylmethyl,cyclobutyl, cyclopentyl, cyclopen-tylethyl, cyclohexylethyl andcyclohexyl, among others. In certain embodiments, the alkyl group isend-capped with a halogen group (Br, Cl, F, or I).

The term “lower alkyl” refers to methyl, ethyl or propyl

The term “lower alkoxy” refers to methoxy, ethoxy or propoxy.

In any of the embodiments described herein, the W, X, Y, Z, G, G′, R,R′, R″, Q1-Q4, A, and Rn can independently be covalently coupled to alinker and/or a linker to which is attached one or more PTM, ULM, ILM orILM′ groups.

Exemplary MLMs

In certain additional embodiments, the MLM of the bifunctional compoundcomprises chemical moieties such as substituted imidazolines,substituted spiro-indolinones, substituted pyrrolidines, substitutedpiperidinones, substituted morpholinones, substitutedpyrrolopyrimidines, substituted imidazolopyridines, substitutedthiazoloimidazoline, substituted pyrrolopyrrolidinones, and substitutedisoquinolinones.

In additional embodiments, the MLM comprises the core structuresmentioned above with adjacent bis-aryl substitutions positioned as cis-or trans-configurations.

In still additional embodiments, the MLM comprises part of structuralfeatures as in RG7112, RG7388, SAR405838, AMG-232, AM-7209, DS-5272,MK-8242, and NVP-CGM-097, and analogs or derivatives thereof.

In certain preferred embodiments, MLM is a derivative of substitutedimidazoline represented as Formula (A-1), or thiazoloimidazolinerepresented as Formula (A-2), or spiro indolinone represented as Formula(A-3), or pyrollidine represented as Formula (A-4), orpiperidinone/morphlinone represented as Formula (A-5), or isoquinolinonerepresented as Formula (A-6), or pyrollopyrimidine/imidazolopyridinerepresented as Formula (A-7), orpyrrolopyrrolidinone/imidazolopyrrolidinone represented as Formula(A-8).

wherein above Formula (A-1) through Formula (A-8),X of Formula (A-1) through Formula (A-8) is selected from the groupconsisting of carbon, oxygen, sulfur, sulfoxide, sulfone, and N—R^(a);

-   -   R^(a) is independently H or an alkyl group with carbon number 1        to 6;        Y and Z of Formula (A-1) through Formula (A-8) are independently        carbon or nitrogen;        A, A′ and A″ of Formula (A-1) through Formula (A-8) are        independently selected from C, N, O or S, can also be one or two        atoms forming a fused bicyclic ring, or a 6,5- and 5,5-fused        aromatic bicyclic group;        R₁, R₂ of Formula (A-1) through Formula (A-8) are independently        selected from the group consisting of an aryl or heteroaryl        group, a heteroaryl group having one or two heteroatoms        independently selected from sulfur or nitrogen, wherein the aryl        or heteroaryl group can be mono-cyclic or bi-cyclic, or        unsubstituted or substituted with one to three substituents        independently selected from the group consisting of:    -   halogen, —CN, C₁ to C₆ alkyl group, C₃ to C₆ cycloalkyl, —OH,        alkoxy with 1 to 6 carbons, fluorine substituted alkoxy with 1        to 6 carbons, sulfoxide with 1 to 6 carbons, sulfone with 1 to 6        carbons, ketone with 2 to 6 carbons, amides with 2 to 6 carbons,        and dialkyl amine with 2 to 6 carbons;        R₃, R₄ of Formula (A-1) through Formula (A-8) are independently        selected from the group consisting of H, methyl and C1 to C6        alkyl;        R₅ of Formula (A-1) through Formula (A-8) is selected from the        group consisting of an aryl or heteroaryl group, a heteroaryl        group having one or two heteroatoms independently selected from        sulfur or nitrogen, wherein the aryl or heteroaryl group can be        mono-cyclic or bi-cyclic, or unsubstituted or substituted with        one to three substituents independently selected from the group        consisting of:    -   halogen, —CN, C1 to C6 alkyl group, C3 to C6 cycloalkyl, —OH,        alkoxy with 1 to 6 carbons, fluorine substituted alkoxy with 1        to 6 carbons, sulfoxide with 1 to 6 carbons, sulfone with 1 to 6        carbons, ketone with 2 to 6 carbons, amides with 2 to 6 carbons,        dialkyl amine with 2 to 6 carbons, alkyl ether (C2 to C6), alkyl        ketone (C3 to C6), morpholinyl, alkyl ester (C3 to C6), alkyl        cyanide (C3 to C6);        R₆ of Formula (A-1) through Formula (A-8) is H or —C(═O)R^(b),        wherein

R^(b) of Formula (A-1) through Formula (A-8) is selected from the groupconsisting of alkyl, cycloalkyl, mono-, di- or tri-substituted aryl orheteroaryl, 4-morpholinyl, 1-(3-oxopiperazunyl), 1-piperidinyl,4-N—R^(C)-morpholinyl, 4-R^(c)-1-piperidinyl, and 3-R^(c)-1-piperidinyl,wherein

R^(c) of Formula (A-1) through Formula (A-8) is selected from the groupconsisting of alkyl, fluorine substituted alkyl, cyano alkyl,hydroxyl-substituted alkyl, cycloalkyl, alkoxyalkyl, amide alkyl, alkylsulfone, alkyl sulfoxide, alkyl amide, aryl, heteroaryl, mono-, bis- andtri-substituted aryl or heteroaryl, CH₂CH₂R^(d), and CH₂CH₂CH₂R^(d),wherein

R^(d) of Formula (A-1) through Formula (A-8) is selected from the groupconsisting of alkoxy, alkyl sulfone, alkyl sulfoxide, N-substitutedcarboxamide, —NHC(O)-alkyl, —NH—SO₂-alkyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl;

R₇ of Formula (A-1) through Formula (A-8) is selected from the groupconsisting of H, C₁ to C₆ alkyl, cyclic alkyl, fluorine substitutedalkyl, cyano substituted alkyl, 5- or 6-membered hetero aryl or aryl,substituted 5- or 6-membered hetero aryl or aryl;R₈ of Formula (A-1) through Formula (A-8) is selected from the groupconsisting of —R^(e)—C(O)—R^(f), —R^(e)-alkoxy, —R^(e)-aryl,—R^(e)-heteroaryl, and —R^(e)—C(O)—R^(f)—C(O)—R^(g), wherein:

R^(e) of Formula (A-1) through Formula (A-8) is an alkylene with 1 to 6carbons, or a bond;

R^(f) of Formula (A-1) through Formula (A-8) is a substituted 4- to7-membered heterocycle;

-   -   R^(g) of Formula (A-1) through Formula (A-8) is selected from        the group consisting of aryl, hetero aryl, substituted aryl or        heteroaryl, and 4- to 7-membered heterocycle;        R₉ of Formula (A-1) through Formula (A-8) is selected from the        group consisting of a mono-, bis- or tri-substituent on the        fused bicyclic aromatic ring in Formula (A-3), wherein the        substitutents are independently selected from the group        consisting of halogen, alkene, alkyne, alkyl, unsubstituted or        substituted with Cl or F;        R₁₀ of Formula (A-1) through Formula (A-8) is selected from the        group consisting of an aryl or heteroaryl group, wherein the        heteroaryl group can contain one or two heteroatoms as sulfur or        nitrogen, aryl or heteroaryl group can be mono-cyclic or        bi-cyclic, the aryl or heteroaryl group can be unsubstituted or        substituted with one to three substituents, including a halogen,        F, Cl, —CN, alkene, alkyne, C1 to C6 alkyl group, C1 to C6        cycloalkyl, —OH, alkoxy with 1 to 6 carbons, fluorine        substituted alkoxy with 1 to 6 carbons, sulfoxide with 1 to 6        carbons, sulfone with 1 to 6 carbons, ketone with 2 to 6        carbons;        R₁₁ of Formula (A-1) through Formula (A-8) is        —C(O)—N(R^(h))(R^(i)), wherein R^(h) and R^(i) are selected from        groups consisting of the following:    -   H, C₁ to C₆ alkyl, alkoxy substituted alkyl, sulfone substituted        alkyl, aryl, heterol aryl, mono-, bis- or tri-substituted aryl        or hetero aryl, alkyl carboxylic acid, heteroaryl carboxylic        acid, alkyl carboxylic acid, fluorine substituted alkyl        carboxylic acid, aryl substituted cycloalkyl, hetero aryl        substituted cycloalkyl; wherein    -   R^(h) and R^(i) of Formula (A-1) through Formula (A-8) are        independently selected from the group consisting of H, connected        to form a ring, 4-hydroxycyclohehexane; mono- and di-hydroxy        substituted alkyl (C₃ to C₆); 3-hydroxycyclobutane;        phenyl-4-carboxylic acid, and substituted phenyl-4-carboxylic        acid;        R₁₂ and R₁₃ of Formula (A-1) through Formula (A-8) are        independently selected from H, lower alkyl (C₁ to C₆), lower        alkenyl (C₂ to C₆), lower alkynyl (C₂ to C₆), cycloalkyl (4, 5        and 6-membered ring), substituted cycloalkyl, cycloalkenyl,        substituted cycloalkenyl, 5- and 6-membered aryl and heteroaryl,        R¹² and R¹³ can be connected to form a 5- and 6-membered ring        with or without substitution on the ring;        R₁₄ of Formula (A-1) through Formula (A-8) is selected from the        group consisting of alkyl, substituted alkyl, alkenyl,        substituted alkenyl, aryl, substituted aryl, heteroaryl,        substituted heteroaryl, heterocycle, substituted heterocycle,        cycloalkyl, substituted cycloalkyl, cycloalkenyl and substituted        cycloalkenyl;        R₁₅ of Formula (A-1) through Formula (A-8) is CN;        R₁₆ of Formula (A-1) through Formula (A-8) is selected from the        group consisting of C1-6 alkyl, C2-6 alkenyl, C1-C6 alkyl-C1-C6        cycloalkyl (e.g., C1-C3 alkyl-C3-C6 cycloalky, C1-C6 alkyl-C3-C6        cycloalkyl), C1-6 alkyl or C3-6 cycloalkyl with one or multiple        hydrogens replaced by fluorine, alkyl or cycloalkyl with one CH₂        replaced by S(═O), —S, or —S(═O)₂, alkyl or cycloalkyl with        terminal CH₃ replaced by S(═O)₂N(alkyl)(alkyl),        —C(═O)N(alkyl)(alkyl), —N(alkyl)S(═O)₂(alkyl), —C(═O)₂(allkyl),        —O(alkyl), C1-6 alkyl or alkyl-cycloalkyl with hydrogen replaced        by hydroxyl group, a 3 to 7 membered cycloalkyl or        heterocycloalkyl, optionally containing a —(C=0)- group, or a 5        to 6 membered aryl or heteroaryl group, which heterocycloalkyl        or heteroaryl group can contain from one to three heteroatoms        independently selected from O, N or S, and the cycloalkyl,        heterocycloalkyl, aryl or heteroaryl group can be unsubstituted        or substituted with from one to three substituents independently        selected from halogen, C1-6 alkyl groups, hydroxylated C1-6        alkyl, C1-6 alkyl containing thioether, ether, sulfone,        sulfoxide, fluorine substituted ether or cyano group;        R₁₇ of Formula (A-1) through Formula (A-8) is selected from the        group consisting of (CH₂)_(n)C(O)NR^(k)R^(l), wherein R^(k) and        R^(l) are independently selected from H, C1-6 alkyl,        hydroxylated C1-6 alkyl, C1-6 alkoxy alkyl, C1-6 alkyl with one        or multiple hydrogens replaced by fluorine, C1-6 alkyl with one        carbon replaced by S(O), S(O)(O), C1-6 alkoxyalkyl with one or        multiple hydrogens replaced by fluorine, C1-6 alkyl with        hydrogen replaced by a cyano group, 5 and 6 membered aryl or        heteroaryl, aklyl aryl with alkyl group containing 1-6 carbons,        and alkyl heteroaryl with alkyl group containing 1-6 carbons,        wherein the aryl or heteroaryl group can be further substituted;        R₁₈ of Formula (A-1) through Formula (A-8) is selected from the        group consisting of substituted aryl, heteroaryl, alkyl,        cycloalkyl, the substitution is preferably —N(C1-4        alkyl)(cycloalkyl), —N(C1-4 alkyl)alkyl-cycloalkyl, and —N(C1-4        alkyl)[(alkyl)-(heterocycle-substituted)-cycloalkyl]; R₁₉ of        Formula (A-1) through Formula (A-8) is selected from the group        consisting of aryl, heteroaryl, bicyclic heteroaryl, and these        aryl or hetroaryl groups can be substituted with halogen, C1-6        alkyl, C1-6 cycloalkyl, CF₃, F, CN, alkyne, alkyl sulfone, the        halogen substitution can be mon- bis- or tri-substituted;        R₂₀ and R₂₁ of Formula (A-1) through Formula (A-8) are        independently selected from C1-6 alkyl, C1-6 cycloalkyl, C1-6        alkoxy, hydoxylated C1-6 alkoxy, and fluorine substituted C1-6        alkoxy, wherein R₂₀ and R₂₁ can further be connected to form a        5, 6 and 7-membered cyclic or heterocyclic ring, which can        further be substituted;        R₂₂ of Formula (A-1) through Formula (A-8) is selected from the        group consisting of H, C1-6 alkyl, C1-6 cycloalkyl, carboxylic        acid, carboxylic acid ester, amide, reverse amide, sulfonamide,        reverse sulfonamide, N-acyl urea, nitrogen-containing 5-membered        heterocycle, the 5-membered heterocycles can be further        substituted with C1-6 alkyl, alkoxy, fluorine-substituted alkyl,        CN, and alkylsulfone;        R₂₃ of Formula (A-1) through Formula (A-8) is selected from        aryl, heteroaryl, —O-aryl, —O— heteroaryl, —O-alkyl,        —O-alkyl-cycloalkyl, —NH-alkyl, —NH-alkyl-cycloalkyl,        —N(H)-aryl, —N(H)— heteroaryl, —N(alkyl)-aryl,        —N(alkyl)-heteroaryl, the aryl or heteroaryl groups can be        substituted with halogen, C1-6 alkyl, hydoxylated C1-6 alkyl,        cycloalkyl, fluorine-substituted C1-6 alkyl, CN, alkoxy, alkyl        sulfone, amide and sulfonamide;        R₂₄ of Formula (A-1) through Formula (A-8) is selected from the        group consisting of —CH2-(C1-6 alkyl), —CH2-cycloalkyl,        —CH2-aryl, CH2-heteroaryl, where alkyl, cycloalkyl, aryl and        heteroaryl can be substituted with halogen, alkoxy, hydoxylated        alkyl, cyano-substituted alkyl, cycloalyl and substituted        cycloalkyl;        R₂₅ of Formula (A-1) through Formula (A-8) is selected from the        group consisting of C1-6 alkyl, C1-6 alkyl-cycloalkyl,        alkoxy-substituted alkyl, hydroxylated alkyl, aryl, heteroaryl,        substituted aryl or heteroaryl, 5,6,and 7-membered        nitrogen-containing saturated heterocycles, 5,6-fused and        6,6-fused nitrogen-containing saturated heterocycles and these        saturated heterocycles can be substituted with C1-6 alkyl,        fluorine-substituted C1-6 alkyl, alkoxy, aryl and heteroaryl        group; R₂₆ of Formula (A-1) through Formula (A-8) is selected        from the group consisting of C1-6 alkyl, C3-6 cycloalkyl, the        alkyl or cycloalkyl can be substituted with —OH, alkoxy,        fluorine-substituted alkoxy, fluorine-substituted alkyl, —NH₂,        —NH-alkyl, NH—C(O)alkyl, —NH—S(O)₂-alkyl, and —S(O)₂-alkyl;        R₂₇ of Formula (A-1) through Formula (A-8) is selected from the        group consisting of aryl, heteroaryl, bicyclic heteroaryl,        wherein the aryl or heteroaryl groups can be substituted with        C1-6 alkyl, alkoxy, NH2, NH-alkyl, halogen, or —CN, and the        substitution can be independently mono-, bis- and        tri-substitution;        R₂₈ of Formula (A-1) through Formula (A-8) is selected from the        group consisting of aryl, 5 and 6-membered heteroaryl, bicyclic        heteroaryl, cycloalkyl, saturated heterocycle such as        piperidine, piperidinone, tetrahydropyran, N-acyl-piperidine,        wherein the cycloalkyl, saturated heterocycle, aryl or        heteroaryl can be further substituted with —OH, alkoxy, mono-,        bis- or tri-substitution including halogen, —CN, alkyl sulfone,        and fluorine substituted alkyl groups; and R_(1″) of Formula        (A-1) through Formula (A-8) is selected from the group        consisting of alkyl, aryl substituted alkyl, alkoxy substituted        alkyl, cycloalkyl, aryl-substituted cycloalkyl, and alkoxy        substituted cycloalkyl.

In certain embodiments, the heterocycles in R^(f) and R^(g) of Formula(A-1) through Formula (A-8) are substituted pyrrolidine, substitutedpiperidine, substituted piperizine.

More specifically, non-limiting examples of MLMs include those shownbelow as well as those ‘hybrid’ molecules that arise from thecombination of 1 or more of the different features shown in themolecules below.

Using MLM in Formula A-1 through A-8, the following PROTACs can beprepared to target a particular protein for degradation, where ‘L” is aconnector (i.e. a linker group), and “PTM” is a ligand binding to atarget protein.

In certain embodiments, the description provides a bifunctional moleculecomprising a structure selected from the group consisting of:

wherein X, R^(a), Y, Z, A, A′, A″, R₁, R₂, R₃, R₄, R₅, R₆, R^(b), R^(c),R^(d), R₇, R^(e), R^(f), R^(g), R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆,R₁₇, R^(k), R^(l), R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, R₂₃,R₂₄, R₂₅, R₂₆, R₂₇, R₂₈,and R_(1″) are as defined herein with regard to Formulas (A-1) through(A-8).

In certain embodiments, the description provides bifunctional orchimeric molecules with the structure: PTM-L-MLM, wherein PTM is aprotein target binding moiety coupled to an MLM by L, wherein L is abond (i.e., absent) or a chemical linker. In certain embodiments, theMLM has a structure selected from the group consisting of A-1-1, A-1-2,A-1-3, and A-1-4:

wherein:R1′ and R2′ of Formulas A-1-1 throught A-1-4 (i.e., A-1-1, A-1-2, A-1-3,and A-1-4) are independently selected from the group consisting of F,Cl, Br, I, acetylene, CN, CF₃ and NO₂;R3′ is selected from the group consisting of —OCH₃, —OCH₂CH₃, —OCH₂CH₂F,—OCH₂CH₂OCH₃, and —OCH(CH₃)₂;R4′ of Formulas A-1-1 throught A-1-4 is selected from the groupconsisting of H, halogen, —CH₃, —CF₃, —OCH₃, —C(CH₃)₃, —CH(CH₃)₂,-cyclopropyl, —CN, —C(CH₃)₂OH, —C(CH₃)₂OCH₂CH₃, —C(CH₃)₂CH₂OH,—C(CH₃)₂CH₂OCH₂CH₃, —C(CH₃)₂CH₂OCH₂CH₂OH, —C(CH₃)₂CH₂OCH₂CH₃,—C(CH₃)₂CN, —C(CH₃)₂C(O)CH₃, —C(CH₃)₂C(O)NHCH₃, —C(CH₃)₂C(O)N(CH₃)₂,—SCH₃, —SCH₂CH₃, —S(O)₂CH₃, —S(O)₂CH₂CH₃, —NHC(CH₃)₃, —N(CH₃)₂,pyrrolidinyl, and 4-morpholinyl;R5′ of Formulas A-1-1 throught A-1-4 is selected from the groupconsisting of halogen, -cyclopropyl, —S(O)₂CH₃, —S(O)₂CH₂CH₃,1-pyrrolidinyl, —NH₂, —N(CH₃)₂, and —NHC(CH₃)₃; andR6′ of Formulas A-1-1 throught A-1-4 is selected from the structurespresented below where the linker connection point is indicated as “*”.Beside R6′ as the point for linker attachment, R4′ can also serve as thelinker attachment position. In the case that R4′ is the linkerconnection site, linker will be connected to the terminal atom of R4′groups shown above.

In certain embodiments, the linker connection position of Formulas A-1-1throught A-1-4 is at least one of R4′ or R6′ or both.

In certain embodiments, R6′ of Formulas A-1-1 throught A-1-4 isindependently selected from the group consisting of H,

wherein “*” indicates the point of attachment of the linker.

In certain embodiments, the linker of Formula A-4-1 through A-4-6 isattached to at least one of R1′, R2′, R3′, R4′, R5′, R6′, or acombination thereof.

In certain embodiments, the description provides bifunctional orchimeric molecules with the structure: PTM-L-MLM, wherein PTM is aprotein target binding moiety coupled to an MLM by L, wherein L is abond (i.e., absent) or a chemical linker. In certain embodiments, theMLM has a structure selected from the group consisting of A-4-1, A-4-2,A-4-3, A-4-4, A-4-5, and A-4-6:

wherein:R7′ of Formula A-4-1 through A-4-6 (i.e., A-4-1, A-4-2, A-4-3, A-4-4,A-4-5, and A-4-6) is a member selected from the group consisting ofhalogen, mono-, and di- or tri-substituted halogen;R8′ of Formula A-4-1 through A-4-6 is selected from the group consistingof H, —F, —Cl, —Br, —I, —CN, —NO₂, ethylnyl, cyclopropyl, methyl, ethyl,isopropyl, vinyl, methoxy, ethoxy, isopropoxy, —OH, other C1-6 alkyl,other C1-6 alkenyl, and C1-6 alkynyl, mono-, di- or tri-substituted;R9′ of Formula A-4-1 through A-4-6 is selected from the group consistingof alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, aryl, substituted aryl, hetero aryl, substitutedheteroaryl, cycloalkyl, substituted cycloalkyl, alkenyl, and substitutedcycloalkenyl;Z of Formula A-4-1 through A-4-6 is selected from the group consistingof H, —OCH₃, —OCH₂CH₃, and halogen;R10′ and R11′ of Formula A-4-1 through A-4-6 are each independentlyselected from the group consisting of H, (CH₂)_(n)—R′, (CH₂)_(n)—NR′R″,(CH₂)_(n)—NR′COR″, (CH₂)_(n)—NR′SO₂R″, (CH₂)_(n)—COOH, (CH₂)_(n)—COOR′,(CH)_(n)—CONR′R″, (CH₂)_(n)—OR′, (CH₂)_(n)—SR′, (CH₂)_(n)—SOR′,(CH₂)_(n)—CH(OH)—R′, (CH₂)_(n)—COR′, (CH₂)_(n)—SO₂R′, (CH₂)_(n)—SONR′R″,(CH₂)_(n)—SO₂NR′R″, (CH₂CH₂O)_(m)—(CH₂)_(n)—R′,(CH₂CH₂O)_(m)—(CH₂)_(n)—OH, (CH₂CH₂O)_(n)—(CH₂)_(n)—OR′,(CH₂CH₂O)_(m)—(CH₂)_(n)—NR′R″, (CH₂CH₂O)_(m)—(CH₂)_(n)—NR′COR″,(CH₂CH₂O)_(m)(CH₂)_(n)—NR′SO₂R″, (CH₂CH₂O)_(m)(CH₂)_(n)—COOH,(CH₂CH₂O)_(m)(CH₂)_(n)—COOR′, (CH₂CH₂O)_(m)—(CH₂)_(n)—CONR′R″,(CH₂CH₂O)_(m)—(CH₂)_(n)—SO₂R′, (CH₂CH₂O)_(m)—(CH₂)_(n)—COR′,(CH₂CH₂O)_(m)—(CH₂)_(n)—SONR′R″, (CH₂CH₂O)_(m)—(CH₂)_(n)—SO₂NR′R″,(CH₂)_(p)—(CH₂CH₂O)_(m)—(CH₂)_(n)R′,(CH₂)_(p)—(CH₂CH₂O)_(m)—(CH₂)_(n)—OH,(CH₂)_(p)—(CH₂CH₂O)_(m)—(CH₂)_(n)—OR′,(CH₂)_(p)—(CH₂CH₂O)_(m)—(CH₂)_(n)—NR′R″,(CH₂)_(p)—(CH₂CH₂O)_(m)—(CH₂)_(n)—NR′COR″,(CH₂)_(p)—(CH₂CH₂O)_(m)—(CH₂)_(n)—NR′SO₂R″,(CH₂)_(p)—(CH₂CH₂O)_(m)—(CH₂)_(n)—COOH, (CH₂)_(p)—(CH₂CH₂O)_(m)(CH₂)_(n)—COOR′, (CH₂)_(p)—(CH₂CH₂O)_(m)—(CH₂)_(n)—CONR′R″,(CH₂)_(p)—(CH₂CH₂O)_(m)—(CH₂)_(n)—SO₂R′,(CH₂)_(p)—(CH₂CH₂O)_(m)—(CH₂)_(n)—COR′,(CH₂)_(p)—(CH₂CH₂O)_(m)—(CH₂)_(n)—SONR′R″,(CH₂)_(p)—(CH₂CH₂O)_(m)—(CH₂)_(n)—SO₂NR′R″, Aryl-(CH₂)_(n)—COOH, andheteroaryl-alkyl-CO-alkyl-NR′R″m, wherein the alkyl may be substitutedwith OR′, and heteroaryl-(CH₂)_(n)-heterocycle wherein the heterocyclemay optionally be substituted with alkyl, hydroxyl, COOR¹ and COR′;wherein R′ and R″ are selected from H, alkyl, alkyl substituted withhalogen, hydroxyl, NH2, NH(alkyl), N(alkyl)₂, oxo, carboxy, clcloalkyland heteroaryl;m, n, and p are independently 0 to 6;R12′ of Formula A-4-1 through A-4-6 is selected from the groupconsisting of —O-(alkyl), —O-(alkyl)-akoxy, —C(O)-(alkyl),—C(OH)-alkyl-alkoxy, —C(O)—NH-(alkyl), —C(O)—N-(alkyl)₂, —S(O)-(alkyl),S(O)₂-(alkyl), —C(O)-(cyclic amine), and —O-aryl-(alkyl),—O-aryl-(alkoxy);R1″ of Formula A-4-1 through A-4-6 is selected from the group consistingof alkyl, aryl substituted alkyl, aloxy substituted alkyl, cycloalkyl,ary-substituted cycloalkyl, and alkoxy substituted cycloalkyl.

In any of the aspects or embodiments described herein, the alkyl, alkoxyor the like can be a lower alkyl or lower alkoxy.

In certain embodiments, the linker connection position of Formula A-4-1through A-4-6 is at least one of Z, R8′, R9′, R10′, R11″, R12″, or R1″.

The method used to design chimeric molecules as presented in A-1-1through A-1-4, A-4-1 through A-4-6 can be applied to MLM with formulaA-2, A-3, A-5, A-6, A-7 and A-8, wherein the solvent exposed area in theMLM can be connected to linker “L” which will be attached to targetprotein ligand “PTM”, to construct PROTACs.

Exemplary MDM2 binding moieties include, but not limited, the following:

The HDM2/MDM2 inhibitors identified in Vassilev, et al., In vivoactivation of the p53 pathway by small-molecule antagonists of MDM2,SCIENCE vol: 303, pag: 844-848 (2004), and Schneekloth, et al., Targetedintracellular protein degradation induced by a small molecule: En routeto chemical proteomics, Bioorg. Med. Chem. Lett. 18 (2008) 5904-5908,including (or additionally) the compounds nutlin-3, nutlin-2, andnutlin-1 (derivatized) as described below, as well as all derivativesand analogs thereof:

(derivatized where a linker group L or a -(L-MLM)group is attached, forexample, at the methoxy group or as a hydroxyl group);

(derivatized where a linker group L or a -(L-MLM) group is attached, forexample, at the methoxy group or hydroxyl group); and

(derivatized where a linker group L or a -(L-MLM) group is attached, forexample, via the methoxy group or as a hydroxyl group).

Exemplary CLMs

Neo-Imide Compounds

In one aspect the description provides compounds useful for bindingand/or inhibiting cereblon. In certain embodiments, the compound isselected from the group consisting of chemical structures:

wherein:

-   -   W of Formulas (a) through (e) is independently selected from the        group CH₂, CHR, C═O, SO₂, NH, and N-alkyl;    -   X of Formulas (a) through (e) is independently selected from the        group O, S and H₂;    -   Y of Formulas (a) through (e) is independently selected from the        group CH₂, —C═CR′, NH, N-alkyl, N-aryl, N-hetaryl, N-cycloalkyl,        N-heterocyclyl, O, and S;    -   Z of Formulas (a) through (e) is independently selected from the        group O, and S or H₂ except that both X and Z cannot be H₂;    -   G and G′ of Formulas (a) through (e) are independently selected        from the group H, optionally substituted linear or branched        alkyl, OH, R′OCOOR, R′OCONRR″, CH₂-heterocyclyl optionally        substituted with R′, and benzyl optionally substituted with R′;    -   Q1-Q4 of Formulas (a) through (e) represent a carbon C        substituted with a group independently selected from R′, N or        N-oxide;    -   A of Formulas (a) through (e) is independently selected from the        group consisting of H, optionally substituted linear or branched        alkyl, cycloalkyl, Cl and F;    -   R of Formulas (a) through (e) comprises, but is not limited to:        —CONR′R″, —OR′, —NR′R″, —SR′, —SO₂R′, —SO₂NR′R″, —CR′R″—,        —CR′NR′R″—, (—CR′O)_(n′)R″, -aryl, -hetaryl, optionally        substituted linear or branched -alkyl, -cycloalkyl,        -heterocyclyl, —P(O)(OR′)R″, P(O)R′R″, —OP(O)(OR′)R″,        —OP(O)R′R″, —Cl, —F, —Br, —I, —CF₃, —CN, —NR′SO₂NR′R″,        —NR′CONR′R″, —CONR′COR″, —NR′C(═N—CN)NR′R″, —C(═N—CN)NR′R″,        —NR′C(═N—CN)R″, —NR′C(═C—NO₂)NR′R″, —SO₂NR′COR″, —NO₂, —CO₂R′,        —C(C═N—OR′)R″, —CR′═CR′R″, —CCR′, —S(C═O)(C═N—R′)R″, —SF₅ and        —OCF₃    -   R′ and R″ of Formulas (a) through (e) are independently selected        from a bond, H, alkyl, cycloalkyl, aryl, heteroaryl,        heterocyclic, —C(═O)R, heterocyclyl, each of which is optionally        substituted;    -   N′ of Formulas (a) through (e) is an integer from 1-10 (e.g.,        1-4, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10);        of Formulas (a) through (e) represents a bond that may be        stereospecific ((R) or (S)) or non-stereospecific; and    -   R_(n) of Formulas (a) through (e) comprises from 1 to 4        independently selected functional groups or atoms, for example,        O, OH, N, C1-C6 alkyl, C1-C6 alkoxy, -alkyl-aryl (e.g., an        -alkyl-aryl comprising at least one of C1-C6 alkyl, C4-C7 aryl,        or a combination thereof), aryl (e.g., C5-C7 aryl), amine,        amide, or carboxy.

Exemplary CLMs

In any of the compounds described herein, the CLM comprises a chemicalstructure selected from the group:

wherein:

-   -   W of Formulas (a) through (e) is independently selected from the        group CH₂, CHR, C═O, SO₂, NH, and N-alkyl;    -   X of Formulas (a) through (e) is independently selected from the        group O, S and H2;    -   Y of Formulas (a) through (e) is independently selected from the        group CH₂, —C═CR′, NH, N-alkyl, N-aryl, N-hetaryl, N-cycloalkyl,        N-heterocyclyl, O, and S;    -   Z of Formulas (a) through (e) is independently selected from the        group O, and S or H₂ except that both X and Z cannot be H₂;    -   G and G′ of Formulas (a) through (e) are independently selected        from the group H, optionally substituted linear or branched        alkyl, OH, R′OCOOR, R′OCONRR″, CH₂-heterocyclyl optionally        substituted with R′, and benzyl optionally substituted with R′;    -   Q1-Q4 of Formulas (a) through (e) represent a carbon C        substituted with a group independently selected from R′, N or        N-oxide;    -   A of Formulas (a) through (e) is independently selected from the        group consisting of a H, optionally substituted linear or        branched alkyl, cycloalkyl, Cl and F;    -   R of Formulas (a) through (e) comprises, but is not limited to:        —CONR′R″, —OR′, —NR′R″, —SR′, —SO₂R′, —SO₂NR′R″, —CR′R″—,        —CR′NR′R″—, -aryl, -hetaryl, -alkyl, -cycloalkyl, -heterocyclyl,        —P(O)(OR′)R″, —P(O)R′R″, —OP(O)(OR′)R″, —OP(O)R′R″, —Cl, —F,        —Br, —I, —CF₃, —CN, —NR′SO₂NR′R″, —NR′CONR′R″, —CONR′COR″,        —NR′C(═N—CN)NR′R″, —C(═N—CN)NR′R″, —NR′C(═N—CN)R″,        —NR′C(═C—NO₂)NR′R″, —SO₂NR′COR″, —NO₂, —CO₂R′, —C(C═N—OR′)R″,        —CR′═CR′R″, —CCR′, —S(C═O)(C═N—R′)R″, —SF₅ and —OCF₃    -   R′ and R″ of Formulas (a) through (e) are independently selected        from a bond, H, alkyl, cycloalkyl, aryl, heteroaryl,        heterocyclic, —C(═O)R, heterocyclyl, each of which is optionally        substituted;    -   n of Formulas (a) through (e) is an integer from 1-10 (e.g.,        1-4, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10);        of Formulas (a) through (e) represents a bond that may be        stereospecific ((R) or (S)) or non-stereospecific; and    -   Rn of Formulas (a) through (e) comprises from 1 to 4        independently selected functional groups or atoms, for example,        O, OH, N, C1-C6 alkyl, C1-C6 alkoxy, -alkyl-aryl (e.g., an        -alkyl-aryl comprising at least one of C1-C6 alkyl, C4-C7 aryl,        or a combination thereof), aryl (e.g., C5-C7 aryl), amine,        amide, or carboxy, and optionally, one of which is modified to        be covalently joined to a PTM, a chemical linker group (L), a        ULM, CLM (or CLM′) or combination thereof.

In certain embodiments described herein, the CLM or ULM comprises achemical structure selected from the group:

wherein:

-   -   W of Formula (g) is independently selected from the group CH₂,        C═O, NH, and N-alkyl;    -   R of Formula (g) is independently selected from a H, methyl, or        optionally substituted linear or branched alkyl (e.g.,        optionally substituted linear or branched C1-C6 alkyl);    -   of Formula (g) represents a bond that may be stereospecific ((R)        or (S)) or non-stereospecific; and    -   Rn of Formula (g) comprises from 1 to 4 independently selected        functional groups or atoms, for example, O, OH, N, C1-C6 alkyl,        C1-C6 alkoxy, -alkyl-aryl (e.g., an -alkyl-aryl comprising at        least one of C1-C6 alkyl, C4-C7 aryl, or a combination thereof),        aryl (e.g., C5-C7 aryl), amine, amide, or carboxy, and        optionally, one of which is modified to be covalently joined to        a PTM, a chemical linker group (L), a ULM, CLM (or CLM′) or        combination thereof.

In any of the embodiments described herein, the W, X, Y, Z, G, G′, R,R′, R″, Q1-Q4, A, and Rn of Formulas (a) through (g) can independentlybe covalently coupled to a linker and/or a linker to which is attachedone or more PTM, ULM, CLM or CLM′ groups.

More specifically, non-limiting examples of CLMs include those shownbelow as well as those “hybrid” molecules that arise from thecombination of 1 or more of the different features shown in themolecules below.

In any of the compounds described herein, the CLM comprises a chemicalstructure selected from the group:

wherein:

-   -   W is independently selected from CH₂, CHR, C═O, SO₂, NH, and        N-alkyl;    -   Q₁, Q₂, Q₃, Q₄, Q₅ are each independently represent a carbon C        or N substituted with a group independently selected from R′, N        or N-oxide;    -   R¹ is selected from absent, H, OH, CN, C1-C3 alkyl, C═O;    -   R² is selected from the group absent, H, OH, CN, C1-C3 alkyl,        CHF₂, CF₃, CHO, C(═O)NH₂;    -   R³ is selected from H, alkyl (e.g., C1-C6 or C1-C3 alkyl),        substituted alkyl (e.g., substituted C1-C6 or C1-C3 alkyl),        alkoxy (e.g., C1-C6 or C1-C3 alkoxyl), substituted alkoxy (e.g.,        substituted C1-C6 or C1-C3 alkoxyl);    -   R⁴ is selected from H, alkyl, substituted alkyl;    -   R⁵ and R6 are each independently H, halogen, C(═O)R′, CN, OH,        CF₃;    -   X is C, CH, C═O, or N;    -   X₁ is C═O, N, CH, or CH₂;    -   R′ is selected from H, halogen, amine, alkyl (e.g., C1-C3        alkyl), substituted alkyl (e.g., substituted C1-C3 alkyl),        alkoxy (e.g., C1-C3 alkoxyl), substituted alkoxy (e.g.,        substituted C1-C3 alkoxyl), NR²R³, C(═O)OR², optionally        substituted phenyl;    -   n is 0-4;    -   is a single or double bond; and    -   the CLM is covalently joined to a PTM, a chemical linker group        (L), a ULM, CLM (or CLM′) or combination thereof.

In any aspect or embodiment described herein, the CLM or CLM′ iscovalently joined to a PTM, a chemical linker group (L), a ULM, a CLM, aCLM′, or a combination thereof via an R group (such as, R, R¹, R², R³,R⁴ or R′), W, X, or a Q group (such as, Q₁, Q₂, Q₃, Q₄, or Q₅).

In any of the embodiments described herein, the CLM or CLM′ iscovalently joined to a PTM, a chemical linker group (L), a ULM, a CLM, aCLM′, or a combination thereof via W, X, R, R¹, R², R³, R⁴, R⁵, R′, Q₁,Q₂, Q₃, Q₄, and Q₅.

In any of the embodiments described herein, the W, X, R¹, R², R³, R⁴,R′, Q₁, Q₂, Q₃, Q₄, and Q₅ can independently be covalently coupled to alinker and/or a linker to which is attached to one or more PTM, ULM,ULM′, CLM or CLM′ groups.

More specifically, non-limiting examples of CLMs include those shownbelow as well as “hybrid” molecules or compounds that arise fromcombining 1 or more features of the following compounds:

wherein:

-   -   W is independently selected from the group CH₂, CHR, C═O, SO₂,        NH, and N-alkyl;    -   R¹ is selected from the group absent, H, CH, CN, C1-C3 alkyl;    -   R² is H or a C1-C3 alkyl;    -   R³ is selected from H, alkyl, substituted alkyl, alkoxy,        substituted alkoxy;    -   R⁴ is methyl or ethyl;    -   R⁵ is H or halo;    -   R⁶ is H or halo;    -   R of the CLM is H;    -   R′ is H or an attachment point for a PTM, a PTM′, a chemical        linker group (L), a ULM, a CLM, a CLM′,    -   Q₁ and Q₂ are each independently C or N substituted with a group        independently selected from H or C1-C3 alkyl;    -   is a single or double bond; and    -   Rn comprises a functional group or an atom.

In any of the embodiments described herein, the W, R¹, R², Q₁, Q₂, Q₃,Q₄, and Rn can independently be covalently coupled to a linker and/or alinker to which is attached one or more PTM, ULM, ULM′, CLM or CLM′groups.

In any of the embodiments described herein, the R¹, R², Q₁, Q₂, Q₃, Q₄,and Rn can independently be covalently coupled to a linker and/or alinker to which is attached one or more PTM, ULM, ULM′, CLM or CLM′groups.

In any of the embodiments described herein, the Q₁, Q₂, Q₃, Q₄, and Rncan independently be covalently coupled to a linker and/or a linker towhich is attached one or more PTM, ULM, ULM′, CLM or CLM′ groups.

In any aspect or embodiment described herein, R_(n) is modified to becovalently joined to the linker group (L), a PTM, a ULM, a second CLMhaving the same chemical structure as the CLM, a CLM′, a second linker,or any multiple or combination thereof.

In any aspect or embodiment described herein, the CLM is selected from:

wherein R′ is a halogen and R¹ is as described in any aspect orembodiment described herein.

In certain cases, “CLM” can be imides that bind to cereblon E3 ligase.These imides and linker attachment point can be but not limited to thefollowing structures:

Exemplary VLMs

In certain embodiments of the compounds as described herein, ULM is VLMand comprises a chemical structure selected from the group ULM-a:

wherein:

-   -   where a dashed line indicates the attachment of at least one        PTM, another ULM or VLM or MLM or ILM or CLM (i.e., ULM′ or VLM′        or CLM′ or ILM′ or MLM′), or a chemical linker moiety coupling        at least one PTM, a ULM′ or a VLM′ or a CLM′ or a ILM′ or a MLM′        to the other end of the linker;    -   X¹, X² of Formula ULM-a are each independently selected from the        group of a bond, O, NR^(Y3), CR^(Y3)R^(Y4), C═O, C═S, SO, and        SO₂;    -   R^(Y3), R^(Y4) of Formula ULM-a are each independently selected        from the group of H, linear or branched C1-6 alkyl, optionally        substituted by 1 or more halo, optionally substituted C1-6        alkoxyl (e.g., optionally substituted by 1-3 R^(P) groups);    -   R^(P) of Formula ULM-a is 1, 2, or 3 groups, each independently        selected from the group H, halo, —OH, C1-3 alkyl, C═O;    -   W³ of Formula ULM-a is selected from the group of an optionally        substituted T, an optionally substituted -T-N(R^(1a)R^(1b))X³,        optionally substituted -T-N(R^(1a)R^(1b)), optionally        substituted -T-Aryl, an optionally substituted -T-Heteroaryl, an        optionally substituted T-biheteroaryl, an optionally substituted        -T-Heterocycle, an optionally substituted -T-biheterocycle, an        optionally substituted —NR¹-T-Aryl, an optionally substituted        —NR¹-T-Heteroaryl or an optionally substituted        —NR¹-T-Heterocycle;    -   X³ of Formula ULM-a is C═O, R¹, R^(1a), R^(1b);    -   each of R¹, R^(1a), R^(1b) is independently selected from the        group consisting of H, linear or branched C₁-C₆ alkyl group        optionally substituted by 1 or more halo or —OH groups,        R^(Y3)C═O, R^(Y3)C═S, R^(Y3)SO, R^(Y3)SO₂, N(R^(Y3)R^(Y4))C═O,        N(R^(Y3)R^(Y4))C═S, N(R^(Y3)R^(Y4))SO, and N(R^(Y3)R^(Y4))SO₂;    -   T of Formula ULM-a is selected from the group of an optionally        substituted alkyl, —(CH₂)_(n)— group, wherein each one of the        methylene groups is optionally substituted with one or two        substituents selected from the group of halogen, methyl,        optionally substituted alkoxy, a linear or branched C₁-C₆ alkyl        group optionally substituted by 1 or more halogen, C(O)        NR¹R^(1a), or NR¹R^(1a) or R¹ and R^(1a) are joined to form an        optionally substituted heterocycle, or —OH groups or an amino        acid side chain optionally substituted;    -   W⁴ of Formula ULM-a is an optionally substituted —NR₁-T-Aryl        wherein the aryl group may be optionally substituted with an        optionally substituted 5-6 membered heteroaryl, an optionally        substituted —NR₁-T-Heteroaryl group or an optionally substituted        —NR₁-T-Heterocycle, where —NR₁ is covalently bonded to X² and R¹        is H or CH₃, preferably H.

In any of the embodiments described herein, T is selected from the groupof an optionally substituted alkyl, —(CH₂)_(n)— group, wherein each oneof the methylene groups is optionally substituted with one or twosubstituents selected from the group of halogen, methyl, optionallysubstituted alkoxy, a linear or branched C1-C6 alkyl group optionallysubstituted by 1 or more halogen, C(O) NR¹R^(1a), or NR¹R^(1a) or R¹ andR^(1a) are joined to form an optionally substituted heterocycle, or —OHgroups or an amino acid side chain optionally substituted; and

n is 0 to 6, often 0, 1, 2, or 3, preferably 0 or 1.

In certain embodiments, W⁴ of Formula ULM-a is

wherein R_(14a), R_(14b), are each independently selected from the groupof H, haloalkyl, or optionally substituted alkyl;

In any of the embodiments, W⁵ of Formula ULM-a is selected from thegroup of a phenyl or a 5-10 membered heteroaryl,

R₁₅ of Formula ULM-a is selected from the group of H, halogen, CN, OH,NO₂, N R_(14a)R_(14b), OR_(14a), CONR_(14a)R_(14b), NR_(14a)COR_(14b),SO₂NR_(14a)R_(14b), NR_(14a)SO₂R_(14b), optionally substituted alkyl,optionally substituted haloalkyl, optionally substituted haloalkoxy,optionally substituted aryl, optionally substituted heteroaryl,optionally substituted cycloalkyl, or optionally substitutedcycloheteroalkyl;

In additional embodiments, W⁴ substituents for use in the presentdisclosure also include specifically (and without limitation to thespecific compound disclosed) the W⁴ substituents which are found in theidentified compounds disclosed herein. Each of these W⁴ substituents maybe used in conjunction with any number of W³ substituents which are alsodisclosed herein.

In certain additional embodiments, ULM-a, is optionally substituted by0-3 R^(P) groups in the pyrrolidine moiety. Each R^(P) is independentlyH, halo, —OH, C1-3alkyl, C═O.

In any of the embodiments described herein, the W³, W⁴ of Formula ULM-acan independently be covalently coupled to a linker which is attachedone or more PTM groups.

and wherein the dashed line indicates the site of attachment of at leastone PTM, another ULM (ULM′) or a chemical linker moiety coupling atleast one PTM or a ULM′ or both to ULM.

In certain embodiments, ULM is VHL and is represented by the structure:

wherein:

-   -   W³ of Formula ULM-b is selected from the group of an optionally        substituted aryl, optionally substituted heteroaryl, or

-   -   R₉ and R₁₀ of Formula ULM-b are independently hydrogen,        optionally substituted alkyl, optionally substituted cycloalkyl,        optionally substituted hydroxyalkyl, optionally substituted        heteroaryl, or haloalkyl, or R₉, R₁₀, and the carbon atom to        which they are attached form an optionally substituted        cycloalkyl;    -   R₁₁ of Formula ULM-b is selected from the group of an optionally        substituted heterocyclic, optionally substituted alkoxy,        optionally substituted heteroaryl, optionally substituted aryl,

-   -   R¹² of Formula ULM-b is selected from the group of H or        optionally substituted alkyl;    -   R¹³ of Formula ULM-b is selected from the group of H, optionally        substituted alkyl, optionally substituted alkylcarbonyl,        optionally substituted (cycloalkyl)alkylcarbonyl, optionally        substituted aralkylcarbonyl, optionally substituted        arylcarbonyl, optionally substituted (heterocyclyl)carbonyl, or        optionally substituted aralkyl;    -   R_(14a), R_(14b) of Formula ULM-b, are each independently        selected from the group of H, haloalkyl, or optionally        substituted alkyl;    -   W⁵ of Formula ULM-b is selected from the group of a phenyl or a        5-10 membered heteroaryl,    -   R₁₅ of Formula ULM-b is selected from the group of H, halogen,        CN, OH, NO₂, N R_(14a)R^(14b), OR_(14a), CONR_(14a)R_(14b),        NR_(14a)COR_(14b), SO₂NR_(14a)R_(14b), NR_(14a)SO₂R_(14b),        optionally substituted alkyl, optionally substituted haloalkyl,        optionally substituted haloalkoxy, optionally substituted aryl,        optionally substituted heteroaryl, optionally substituted        cycloalkyl, or optionally substituted cycloheteroalkyl;    -   R₁₆ of Formula ULM-b is independently selected from the group        consisting of halo, optionally substituted alkyl, optionally        substituted haloalkyl, hydroxy, or optionally substituted        haloalkoxy;    -   o of Formula ULM-b is 0, 1, 2, 3, or 4;    -   R₁₈ of Formula ULM-b is independently selected from the group        consisting of H, halo, optionally substituted alkoxy, cyano,        optionally substituted alkyl, haloalkyl, haloalkoxy or a linker;        and    -   p of Formula ULM-b is 0, 1, 2, 3, or 4, and wherein the dashed        line indicates the site of attachment of at least one PTM,        another ULM (ULM′) or a chemical linker moiety coupling at least        one PTM or a ULM′ or both to ULM.

In certain embodiments, R₁₅ of Formula ULM-b is

wherein R₁₇ is H, halo, optionally substituted C₃₋₆cycloalkyl,optionally substituted C₁₋₆alkyl, optionally substituted C₁₋₆alkenyl,and C₁₋₆haloalkyl; and Xa is S or O.

In certain embodiments, R₁₇ of Formula ULM-b is selected from the groupmethyl, ethyl, isopropyl, and cyclopropyl.

In certain additional embodiments, R₁₅ of Formula ULM-b is selected fromthe group consisting of:

In certain embodiments, R₁₁ of Formula ULM-b is selected from the groupconsisting of:

In certain embodiments, ULM has a chemical structure selected from thegroup of:

wherein:

-   -   R₁ of Formulas ULM-c, ULM-d, and ULM-e is H, ethyl, isopropyl,        tert-butyl, sec-butyl, cyclopropyl, cyclobutyl, cyclopentyl, or        cyclohexyl; optionally substituted alkyl, optionally substituted        hydroxyalkyl, optionally substituted heteroaryl, or haloalkyl;    -   R_(14a) of Formulas ULM-c, ULM-d, and ULM-e is H, haloalkyl,        optionally substituted alkyl, methyl, fluoromethyl,        hydroxymethyl, ethyl, isopropyl, or cyclopropyl;    -   R₁₅ of Formulas ULM-c, ULM-d, and ULM-e is selected from the        group consisting of H, halogen, CN, OH, NO₂, optionally        substituted heteroaryl, optionally substituted aryl, optionally        substituted alkyl, optionally substituted haloalkyl, optionally        substituted haloalkoxy, cycloalkyl, or cycloheteroalkyl;    -   X of Formulas ULM-c, ULM-d, and ULM-e is C, CH₂, or C═O    -   R₃ of Formulas ULM-c, ULM-d, and ULM-e is absent or an        optionally substituted 5 or 6 membered heteroaryl; and    -   wherein the dashed line indicates the site of attachment of at        least one PTM, another ULM (ULM′) or a chemical linker moiety        coupling at least one PTM or a ULM′ or both to ULM.

In certain embodiments, ULM comprises a group according to the chemicalstructure:

wherein

R_(14a) of Formula ULM-f is H, haloalkyl, optionally substituted alkyl,methyl, fluoromethyl, hydroxymethyl, ethyl, isopropyl, or cyclopropyl;

R₉ of Formula ULM-f is H;

R₁₀ of Formula ULM-f is H, ethyl, isopropyl, tert-butyl, sec-butyl,cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl;

R₁₁ of Formula ULM-f is

or optionally substituted heteroaryl;

p of Formula ULM-f is 0, 1, 2, 3, or 4;

each R₁₈ of Formula ULM-f is independently halo, optionally substitutedalkoxy, cyano, optionally substituted alkyl, haloalkyl, haloalkoxy or alinker;

R₁₂ of Formula ULM-f is H, C═O;

R₁₃ of Formula ULM-f is H, optionally substituted alkyl, optionallysubstituted alkylcarbonyl, optionally substituted(cycloalkyl)alkylcarbonyl, optionally substituted aralkylcarbonyl,optionally substituted arylcarbonyl, optionally substituted(heterocyclyl)carbonyl, or optionally substituted aralkyl,

R₁₅ of Formula ULM-f is selected from the group consisting of H,halogen, Cl, CN, OH, NO₂, optionally substituted heteroaryl, optionallysubstituted aryl;

wherein the dashed line of Formula ULM-f indicates the site ofattachment of at least one PTM, another ULM (ULM′) or a chemical linkermoiety coupling at least one PTM or a ULM′ or both to ULM.

In certain embodiments, the ULM is selected from the followingstructures:

where n is 0 or 1.

In certain embodiments, the ULM is selected from the followingstructures:

wherein, the phenyl ring in ULM-a1 through ULM-a15, ULM-b1 throughULM-b2, ULM-c1 through ULM-c15 and ULM-d1 through ULM-d9 is optionallysubstituted with fluorine, lower alkyl and alkoxy groups, and whereinthe dashed line indicates the site of attachment of at least one PTM,another ULM (ULM′) or a chemical linker moiety coupling at least one PTMor a ULM′ or both to ULM-a.

In one embodiment, the phenyl ring in ULM-a1 through ULM-a15, ULM-b1through ULM-b12, ULM-c1 through ULM-c15 and ULM-d1 through ULM-d9 can befunctionalized as the ester to make it a part of the prodrug.

In certain embodiments, the hydroxyl group on the pyrrolidine ring ofULM-al through ULM-a15, ULM-b1 through ULM-b12, ULM-c1 through ULM-c15and ULM-d1 through ULM-d9, respectively, comprises an ester-linkedprodrug moiety.

In any of the aspects or embodiments described herein, the ULM and wherepresent, ULM′, are each independently a group according to the chemicalstructure:

wherein:

-   -   R^(1′) of ULM-g is an optionally substituted C₁-C₆ alkyl group,        an optionally substituted —(CH₂)_(n)OH, an optionally        substituted —(CH₂)_(n)SH, an optionally substituted        (CH₂)_(n)—O—(C₁-C₆)alkyl group, an optionally substituted        (CH₂)_(n)—WCOCW—(C₀-C₆)alkyl group containing an epoxide moiety        WCOCW where each W is independently H or a C₁-C₃ alkyl group, an        optionally substituted —(CH₂)_(n)COOH, an optionally substituted        —(CH₂)_(n)C(O)—(C₁-C₆ alkyl), an optionally substituted        —(CH₂)_(n)NHC(O)—R₁, an optionally substituted        —(CH₂)_(n)C(O)—NR₁R², an optionally substituted        —(CH₂)_(n)OC(O)—NR₁R², —(CH₂O)_(n)H, an optionally substituted        —(CH₂)_(n)OC(O)—(C₁-C₆ alkyl), an optionally substituted        —(CH₂)_(n)C(O)—O—(C₁-C₆ alkyl), an optionally substituted        —(CH₂O)_(n)COOH, an optionally substituted —(OCH₂)_(n)O—(C₁-C₆        alkyl), an optionally substituted —(CH₂O)_(n)C(O)—(C₁-C₆ alkyl),        an optionally substituted —(OCH₂)_(n)NHC(O)—R₁, an optionally        substituted —(CH₂O)_(n)C(O)—NR₁R², —(CH₂CH₂O)_(n)H, an        optionally substituted —(CH₂CH₂O)_(n)COOH, an optionally        substituted —(OCH₂CH₂)_(n)O—(C₁-C₆ alkyl), an optionally        substituted —(CH₂CH₂O)_(n)C(O)—(C₁-C₆ alkyl), an optionally        substituted —(OCH₂CH₂)_(n)NHC(O)—R₁, an optionally substituted        —(CH₂CH₂O)_(n)C(O)—NR₁R₂,an optionally substituted —SO₂R_(S), an        optionally substituted S(O)R_(S), NO₂, CN or halogen (F, Cl, Br,        I, preferably F or Cl);    -   R₁ and R₂ of ULM-g are each independently H or a C₁-C₆ alkyl        group which may be optionally substituted with one or two        hydroxyl groups or up to three halogen groups (preferably        fluorine);    -   R_(S) of ULM-g is a C₁-C₆ alkyl group, an optionally substituted        aryl, heteroaryl or heterocycle group or a —(CH₂)_(m)NR₁R₂        group;    -   X and X′ of ULM-g are each independently C═O, C═S, —S(O), S(O)₂,        (preferably X and X′ are both C═O);    -   R^(2′) of ULM-g is an optionally substituted        —(CH₂)_(n)—(C═O)_(u)(NR₁)_(v)(SO₂)_(w)alkyl group, an optionally        substituted —(CH₂)_(n)—(C═O)_(u)(NR₁)_(v)(SO₂)_(w)NR_(1N)R_(2N)        group, an optionally substituted        —(CH₂)_(n)—(C═O)_(u)(NR₁)_(v)(SO₂)_(w)-Aryl, an optionally        substituted —(CH₂)_(n)—(C═O)_(u)(NR₁)_(v)(SO₂)_(w)-Heteroaryl,        an optionally substituted        —(CH₂)_(n)—(C═O)_(v)NR₁(SO₂)_(w)-Heterocycle, an optionally        substituted —NR¹—(CH₂)_(n)—C(O)_(u)(NR₁)_(v)(SO₂)_(w)-alkyl, an        optionally substituted        —NR¹—(CH₂)_(n)—C(O)_(u)(NR₁)_(v)(SO₂)_(w)—NR_(1N)R_(2N), an        optionally substituted        —NR¹—(CH₂)_(n)—C(O)(NR₁)_(v)(SO₂)_(w)—NR₁C(O)R_(1N), an        optionally substituted        —NR¹—(CH₂)_(n)—(C═O)_(u)(NR₁)_(v)(SO₂)_(w)-Aryl, an optionally        substituted        —NR¹—(CH₂)_(n)—(C═O)_(u)(NR₁)_(v)(SO₂)_(w)-Heteroaryl or an        optionally substituted        —NR¹—(CH₂)_(n)—(C═O)_(v)NR₁(SO₂)_(w)-Heterocycle, an optionally        substituted —X^(R2′)-alkyl group; an optionally substituted        —X^(R2′)-Aryl group; an optionally substituted        —X^(R2′)-Heteroaryl group; an optionally substituted        —X^(R2′)-Heterocycle group; an optionally substituted;    -   R^(3′) of ULM-g is an optionally substituted alkyl, an        optionally substituted        —(CH₂)_(n)—(O)_(u)(NR₁)_(v)(SO₂)_(w)-alkyl, an optionally        substituted —(CH₂)_(n)—C(O)_(u)(NR₁)_(v)(SO₂)_(w)—NR₁NR₂N, an        optionally substituted        —(CH₂)_(n)—C(O)_(u)(NR₁)_(v)(SO₂)_(w)—NR₁C(O)R_(1N), an        optionally substituted        —(CH₂)_(n)—C(O)_(u)(NR₁)_(v)(SO₂)_(w)—C(O)NR₁R², an optionally        substituted —(CH₂)_(n)—C(O)_(u)(NR₁)_(v)(SO₂)_(w)-Aryl, an        optionally substituted        —(CH₂)—C(O)_(u)(NR₁)_(v)(SO₂)_(w)-Heteroaryl, an optionally        substituted —(CH₂)—C(O)_(u)(NR₁)_(v)(SO₂)_(w)-Heterocycle, an        optionally substituted        —NR¹—(CH₂)_(n)—C(O)_(u)(NR₁)_(v)(SO₂)_(w)-alkyl, an optionally        substituted —NR¹—(CH₂)_(n)—C(O)_(u)(NR₁)_(v)(SO₂)_(w)—NR₁NR₂N,        an optionally substituted        —NR¹—(CH₂)_(n)—C(O)_(u)(NR₁)_(v)(SO₂)_(w)—NR₁C(O)R^(1N), an        optionally substituted        —NR¹—(CH₂)_(n)—C(O)_(u)(NR₁)_(v)(SO₂)_(w)-Aryl, an optionally        substituted        —NR¹—(CH₂)_(n)—C(O)_(u)(NR₁)_(v)(SO₂)_(w)-Heteroaryl, an        optionally substituted        —NR¹—(CH₂)_(n)—C(O)_(u)(NR₁)_(v)(SO₂)_(w)-Heterocycle, an        optionally substituted        —O—(CH₂)_(n)—(C═O)_(u)(NR₁)_(v)(SO₂)_(w)-alkyl, an optionally        substituted —O—(CH₂)_(n)—(C═O)_(u)(NR₁)_(v)(SO₂)_(w)—NR₁NR₂N, an        optionally substituted        —O—(CH₂)_(n)—(C═O)_(u)(NR₁)_(v)(SO₂)_(w)—NR₁C(O)R^(1N), an        optionally substituted        —O—(CH₂)_(n)—(C═O)_(u)(NR₁)_(v)(SO₂)_(w)-Aryl, an optionally        substituted —O—(CH₂)—(C═O)_(u)(NR₁)_(v)(SO₂)_(w)-Heteroaryl or        an optionally substituted        —O—(CH₂)—(C═O)_(u)(NR₁)_(v)(SO₂)_(w)-Heterocycle;        —(CH₂)_(n)—(V)_(n′)—(CH₂)_(n)—(V)_(n′)-alkyl group, an        optionally substituted        —(CH₂)_(n)—(V)_(n′)—(CH₂)_(n)—(V)_(n′)-Aryl group, an optionally        substituted —(CH₂)_(n)—(V)_(n′)—(CH₂)—(V)_(n′)-Heteroaryl group,        an optionally substituted        —(CH₂)_(n)—(V)_(n′)—(CH₂)_(n)—(V)_(n′)-Heterocycle group, an        optionally substituted        —(CH₂)_(n)—N(R_(1′))(C═O)_(m′)—(V)_(n′)-alkyl group, an        optionally substituted        —(CH₂)_(n)—N(R_(1′))(C═O)_(m′)—(V)_(n′)-Aryl group, an        optionally substituted        —(CH₂)_(n)—N(R_(1′))(C═O)_(m′)—(V)_(n′)-Heteroaryl group, an        optionally substituted        —(CH₂)_(n)—N(R₁)(C═O)_(m′)—(V)_(n′)-Heterocycle group, an        optionally substituted —X^(R3′)-alkyl group; an optionally        substituted —X^(R3′)-Aryl group; an optionally substituted        —X^(R3′)-Heteroaryl group; an optionally substituted        —X^(R3′)-Heterocycle group; an optionally substituted;    -   R_(1N) and R_(2N) of ULM-g are each independently H, C₁-C₆ alkyl        which is optionally substituted with one or two hydroxyl groups        and up to three halogen groups or an optionally substituted        —(CH₂)_(n)-Aryl, —(CH₂)_(n)-Heteroaryl or —(CH₂)_(n)-Heterocycle        group;    -   V of ULM-g is O, S or NR₁;    -   R₁ of ULM-g is the same as above;    -   R¹ and R_(1′) of ULM-g are each independently H or a C₁-C₃ alkyl        group;    -   X^(R2′) and X^(R3′) of ULM-g are each independently an        optionally substituted —CH₂)_(n)—,        —CH₂)_(n)—CH(X_(v))═CH(X_(v))— (cis or trans), —CH₂)_(n)—CH—CH—,        —(CH₂CH₂O)_(n)— or a C₃-C₆ cycloalkyl group, where X_(v) is H, a        halo or a C₁-C₃ alkyl group which is optionally substituted;    -   each m of ULM-g is independently 0, 1, 2, 3, 4, 5, 6;    -   each m′ of ULM-g is independently 0 or 1;    -   each n of ULM-g is independently 0, 1, 2, 3, 4, 5, 6;    -   each n′ of ULM-g is independently 0 or 1;    -   each u of ULM-g is independently 0 or 1;    -   each v of ULM-g is independently 0 or 1;    -   each w of ULM-g is independently 0 or 1; and    -   any one or more of R^(1′), R^(2′), R^(3′), X and X′ of ULM-g is        optionally modified to be covalently bonded to the PTM group        through a linker group when PTM is not ULM′, or when PTM is        ULM′, any one or more of R^(1′), R^(2′), R^(3′), X and X′ of        each of ULM and ULM′ are optionally modified to be covalently        bonded to each other directly or through a linker group, or a        pharmaceutically acceptable salt, stereoisomer, solvate or        polymorph thereof.

In any of the aspects or embodiments described herein, the ULM and whenpresent, ULM′, are each independently a group according to the chemicalstructure:

wherein:

-   -   each of R^(1′), R^(2′) and R^(3′) of ULM-h are the same as above        and X is C═O, C═S, —S(O) group or a S(O)₂ group, more preferably        a C═O group, and    -   any one or more of R^(1′), R^(2′) and R^(3′) of ULM-h are        optionally modified to bind a linker group to which is further        covalently bonded to the PTM group when PTM is not ULM′, or when        PTM is ULM′, any one or more of R^(1′), R^(2′), R^(3′) of each        of ULM and ULM′ are optionally modified to be covalently bonded        to each other directly or through a linker group, or    -   a pharmaceutically acceptable salt, enantiomer, diastereomer,        solvate or polymorph thereof.

In any of the aspects or embodiments described herein, the ULM, and whenpresent, ULM′, are each independently according to the chemicalstructure:

wherein:

-   -   any one or more of R^(1′), R^(2′) and R^(3′) of ULM-I are        optionally modified to bind a linker group to which is further        covalently bonded to the PTM group when PTM is not ULM′, or when        PTM is ULM′, any one or more of R^(1′), R^(2′), R^(3′) of each        of ULM and ULM′ are optionally modified to be covalently bonded        to each other directly or through a linker group, or    -   a pharmaceutically acceptable salt, enantiomer, diastereomer,        solvate or polymorph thereof.

In further preferred aspects of the invention, R^(1′) of ULM-g throughULM-i is preferably a hydroxyl group or a group which may be metabolizedto a hydroxyl or carboxylic group, such that the compound represents aprodrug form of an active compound. Exemplary preferred R^(1′) groupsinclude, for example, —(CH₂)_(n)OH, (CH₂)_(n)—O—(C₁-C₆)alkyl group,—(CH₂)_(n)COOH, —(CH₂O)_(n)H, an optionally substituted—(CH₂)_(n)OC(O)—(C₁-C₆ alkyl), or an optionally substituted—(CH₂)_(n)C(O)—O—(C₁-C₆ alkyl), wherein n is 0 or 1. Where R^(1′) is orcontains a carboxylic acid group, a hydroxyl group or an amine group,the hydroxyl group, carboxylic acid group or amine (each of which may beoptionally substituted), may be further chemically modified to provide acovalent link to a linker group to which the PTM group (including a ULM′group) is bonded;

X and X′, where present, of ULM-g and ULM-h are preferably a C═O, C═S,—S(O) group or a S(O)₂ group, more preferably a C═O group;

R^(2′) of ULM-g through ULM-i is preferably an optionally substituted—NR¹-T-Aryl, an optionally substituted —NR¹-T-Heteroaryl group or anoptionally substituted —NR¹-T-Heterocycle, where R¹ is H or CH₃,preferably H and T is an optionally substituted —(CH₂)_(n)— group,wherein each one of the methylene groups may be optionally substitutedwith one or two substituents, preferably selected from halogen, an aminoacid sidechain as otherwise described herein or a C₁-C₃ alkyl group,preferably one or two methyl groups, which may be optionallysubstituted; and n is 0 to 6, often 0, 1, 2 or 3, preferably 0 or 1.Alternatively, T may also be a —(CH₂O)_(n)— group, a —(OCH₂)_(n)— group,a —(CH₂CH₂O)_(n)— group, a —(OCH₂CH₂)_(n)— group, all of which groupsare optionally substituted.

Preferred Aryl groups for R^(2′) of ULM-g through ULM-i includeoptionally substituted phenyl or naphthyl groups, preferably phenylgroups, wherein the phenyl or naphthyl group is connected to a PTM(including a ULM′ group) with a linker group and/or optionallysubstituted with a halogen (preferably F or Cl), an amine, monoalkyl- ordialkyl amine (preferably, dimethylamine), F, Cl, OH, COOH, C₁-C₆ alkyl,preferably CH₃, CF₃, OMe, OCF₃, NO₂, or CN group (each of which may besubstituted in ortho-, meta- and/or para-positions of the phenyl ring,preferably para-), an optionally substituted phenyl group (the phenylgroup itself is optionally connected to a PTM group, including a ULM′,with a linker group), and/or optionally substituted with at least one ofF, Cl, OH, COOH, CH₃, CF₃, OMe, OCF₃, NO₂, or CN group (in ortho-, meta-and/or para-positions of the phenyl ring, preferably para-), a naphthylgroup, which may be optionally substituted, an optionally substitutedheteroaryl, preferably an optionally substituted isoxazole including amethylsubstituted isoxazole, an optionally substituted oxazole includinga methylsubstituted oxazole, an optionally substituted thiazoleincluding a methyl substituted thiazole, an optionally substitutedisothiazole including a methyl substituted isothiazole, an optionallysubstituted pyrrole including a methylsubstituted pyrrole, an optionallysubstituted imidazole including a methylimidazole, an optionallysubstituted benzimidazole or methoxybenzylimidazole, an optionallysubstituted oximidazole or methyloximidazole, an optionally substituteddiazole group, including a methyldiazole group, an optionallysubstituted triazole group, including a methylsubstituted triazolegroup, an optionally substituted pyridine group, including a halo-(preferably, F) or methylsubstitutedpyridine group or an oxapyridinegroup (where the pyridine group is linked to the phenyl group by anoxygen), an optionally substituted furan, an optionally substitutedbenzofuran, an optionally substituted dihydrobenzofuran, an optionallysubstituted indole, indolizine or azaindolizine (2, 3, or4-azaindolizine), an optionally substituted quinoline, an optionallysubstituted group according to the chemical structure:

wherein:

-   -   S^(c) of ULM-g through ULM-i is CHR^(SS), NR^(URE), or O ;    -   R^(HET) of ULM-g through ULM-i is H, CN, NO₂, halo (preferably        Cl or F), optionally substituted C₁-C₆ alkyl (preferably        substituted with one or two hydroxyl groups or up to three halo        groups (e.g. CF₃), optionally substituted O(C₁-C₆ alkyl)        (preferably substituted with one or two hydroxyl groups or up to        three halo groups) or an optionally substituted acetylenic group        —C≡C—R_(a) where R_(a) is H or a C₁-C₆ alkyl group (preferably        C₁-C₃ alkyl);    -   R^(SS) of ULM-g through ULM-i is H, CN, NO₂, halo (preferably F        or Cl), optionally substituted C₁-C₆ alkyl (preferably        substituted with one or two hydroxyl groups or up to three halo        groups), optionally substituted O—(C₁-C₆ alkyl) (preferably        substituted with one or two hydroxyl groups or up to three halo        groups) or an optionally substituted —C(O)(C₁-C₆alkyl)        (preferably substituted with one or two hydroxyl groups or up to        three halo groups);    -   R^(URE) of ULM-g through ULM-i is H, a C₁-C₆ alkyl (preferably H        or C₁-C₃ alkyl) or a —C(O)(C₁-C₆ alkyl) each of which groups is        optionally substituted with one or two hydroxyl groups or up to        three halogen, preferably fluorine groups, or an optionally        substituted phenyl group, an optionally substituted heteroaryl,        or an optionally substituted heterocycle, preferably for example        piperidine, morpholine, pyrrolidine, tetrahydrofuran);    -   R^(PRO) of ULM-g through ULM-i is H, optionally substituted        C₁-C₆ alkyl or an optionally substituted aryl (phenyl or        napthyl), heteroaryl or heterocyclic group selected from the        group consisting of oxazole, isoxazole, thiazole, isothiazole,        imidazole, diazole, oximidazole, pyrrole, pyrollidine, furan,        dihydrofuran, tetrahydrofuran, thiene, dihydrothiene,        tetrahydrothiene, pyridine, piperidine, piperazine, morpholine,        quinoline, (each preferably substituted with a C₁-C₃ alkyl        group, preferably methyl or a halo group, preferably F or Cl),        benzofuran, indole, indolizine, azaindolizine;    -   R^(PRO1) and R^(PRO2) of ULM-g through ULM-i are each        independently H, an optionally substituted C₁-C₃ alkyl group or        together form a keto group; and    -   each n of ULM-g through ULM-i is independently 0, 1, 2, 3, 4, 5,        or 6 (preferably 0 or 1), or an optionally substituted        heterocycle, preferably tetrahydrofuran, tetrahydrothiene,        piperidine, piperazine or morpholine (each of which groups when        substituted, are preferably substituted with a methyl or halo        (F, Br, Cl), each of which groups may be optionally attached to        a PTM group (including a ULM′ group) via a linker group.

In certain preferred aspects,

of ULM-g through ULM-i is a

group,where R^(PRO) and n of ULM-g through ULM-i are the same as above.

Preferred heteroaryl groups for R^(2′) of ULM-g through ULM-i include anoptionally substituted quinoline (which may be attached to thepharmacophore or substituted on any carbon atom within the quinolinering), an optionally substituted indole, an optionally substitutedindolizine, an optionally substituted azaindolizine, an optionallysubstituted benzofuran, including an optionally substituted benzofuran,an optionally substituted isoxazole, an optionally substituted thiazole,an optionally substituted isothiazole, an optionally substitutedthiophene, an optionally substituted pyridine (2-, 3, or 4-pyridine), anoptionally substituted imidazole, an optionally substituted pyrrole, anoptionally substituted diazole, an optionally substituted triazole, atetrazole, an optionally substituted oximidazole, or a group accordingto the chemical structure:

wherein:

-   -   S^(c) of ULM-g through ULM-i is CHR^(SS), NR^(URE), or O ;    -   R^(HET) of ULM-g through ULM-i is H, CN, NO₂, halo (preferably        Cl or F), optionally substituted C₁-C₆ alkyl (preferably        substituted with one or two hydroxyl groups or up to three halo        groups (e.g. CF₃), optionally substituted O(C₁-C₆ alkyl)        (preferably substituted with one or two hydroxyl groups or up to        three halo groups) or an optionally substituted acetylenic group        —C≡C—R_(a) where R_(a) of ULM-g through ULM-i is H or a C₁-C₆        alkyl group (preferably C₁-C₃ alkyl);    -   R^(SS) of ULM-g through ULM-i is H, CN, NO₂, halo (preferably F        or Cl), optionally substituted C₁-C₆ alkyl (preferably        substituted with one or two hydroxyl groups or up to three halo        groups), optionally substituted O—(C₁-C₆ alkyl) (preferably        substituted with one or two hydroxyl groups or up to three halo        groups) or an optionally substituted —C(O)(C₁-C₆alkyl)        (preferably substituted with one or two hydroxyl groups or up to        three halo groups);    -   R^(URE) of ULM-g through ULM-i is H, a C₁-C₆ alkyl (preferably H        or C₁-C₃ alkyl) or a —C(O)(C₁-C₆ alkyl), each of which groups is        optionally substituted with one or two hydroxyl groups or up to        three halogen, preferably fluorine groups, or an optionally        substituted heterocycle, for example piperidine, morpholine,        pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine,        piperazine, each of which is optionally substituted, and    -   Y^(C) of ULM-g through ULM-i is N or C—R^(YC), where R^(YC) is        H, OH, CN, NO₂, halo (preferably Cl or F), optionally        substituted C₁-C₆ alkyl (preferably substituted with one or two        hydroxyl groups or up to three halo groups (e.g. CF₃),        optionally substituted O(C₁-C₆ alkyl) (preferably substituted        with one or two hydroxyl groups or up to three halo groups) or        an optionally substituted acetylenic group —C≡C—R_(a) where        R_(a) is H or a C₁-C₆ alkyl group (preferably C₁-C₃ alkyl), each        of which groups may be optionally connected to a PTM group        (including a ULM′ group) via a linker group.

Preferred heterocycle groups for R^(2′) of ULM-g through ULM-i includetetrahydrofuran, tetrahydrothiene, tetrahydroquinoline, piperidine,piperazine, pyrrollidine, morpholine, oxane or thiane, each of whichgroups may be optionally substituted, or a group according to thechemical structure:

preferably, a

group,wherein:

-   -   R^(PRO) of ULM-g through ULM-i is H, optionally substituted        C₁-C₆ alkyl or an optionally substituted aryl, heteroaryl or        heterocyclic group;    -   R^(PRO1) and R^(PRO2) of ULM-g through ULM-i are each        independently H, an optionally substituted C₁-C₃ alkyl group or        together form a keto group and    -   each n of ULM-g through ULM-i is independently 0, 1, 2, 3, 4, 5,        or 6 (often 0 or 1), each of which groups may be optionally        connected to a PTM group (including a ULM′ group) via a linker        group.

Preferred R^(2′) substituents of ULM-g through ULM-i also includespecifically (and without limitation to the specific compound disclosed)the R^(2′) substituents which are found in the identified compoundsdisclosed herein (which includes the specific compounds which aredisclosed in the present specification, and the figures which areattached hereto). Each of these R^(2′) substituents may be used inconjunction with any number of R^(3′) substituents which are alsodisclosed herein.

R^(3′) of ULM-g through ULM-i is preferably an optionally substituted-T-Aryl, an optionally substituted-T-Heteroaryl, an optionallysubstituted -T-Heterocycle, an optionally substituted-NR¹-T-Aryl, anoptionally substituted —NR¹-T-Heteroaryl or an optionallysubstituted-NR¹-T-Heterocycle, where R¹ is H or a C₁-C₃ alkyl group,preferably H or CH₃, T is an optionally substituted —(CH₂)_(n)— group,wherein each one of the methylene groups may be optionally substitutedwith one or two substituents, preferably selected from halogen, a C₁-C₃alkyl group or the sidechain of an amino acid as otherwise describedherein, preferably methyl, which may be optionally substituted; and n is0 to 6, often 0, 1, 2, or 3 preferably 0 or 1. Alternatively, T may alsobe a —(CH₂O)_(n)— group, a —(OCH₂)_(n)— group, a —(CH₂CH₂O)_(n)— group,a —(OCH₂CH₂)— group, each of which groups is optionally substituted.

Preferred aryl groups for R^(3′) of ULM-g through ULM-i includeoptionally substituted phenyl or naphthyl groups, preferably phenylgroups, wherein the phenyl or naphthyl group is optionally connected toa PTM group (including a ULM′ group) via a linker group and/oroptionally substituted with a halogen (preferably F or Cl), an amine,monoalkyl- or dialkyl amine (preferably, dimethylamine), an amido group(preferably a —(CH₂)_(m)—NR₁C(O)R₂ group where m, R₁ and R₂ are the sameas above), a halo (often F or Cl), OH, CH₃, CF₃, OMe, OCF₃, NO₂, ,CN ora S(O)₂R_(S) group (R_(S) is a C₁-C₆ alkyl group, an optionallysubstituted aryl, heteroaryl or heterocycle group or a —(CH₂)_(m)NR₁R²group), each of which may be substituted in ortho-, meta- and/orpara-positions of the phenyl ring, preferably para-), or an Aryl(preferably phenyl), Heteroaryl or Heterocycle. Preferably saidsubstituent phenyl group is an optionally substituted phenyl group(i.e., the substituent phenyl group itself is preferably substitutedwith at least one of F, Cl, OH, SH, COOH, CH₃, CF₃, OMe, OCF₃, NO₂, CNor a linker group to which is attached a PTM group (including a ULM′group), wherein the substitution occurs in ortho-, meta- and/orpara-positions of the phenyl ring, preferably para-), a naphthyl group,which may be optionally substituted including as described above, anoptionally substituted heteroaryl (preferably an optionally substitutedisoxazole including a methylsubstituted isoxazole, an optionallysubstituted oxazole including a methylsubstituted oxazole, an optionallysubstituted thiazole including a methyl substituted thiazole, anoptionally substituted pyrrole including a methylsubstituted pyrrole, anoptionally substituted imidazole including a methylimidazole, abenzylimidazole or methoxybenzylimidazole, an oximidazole ormethyloximidazole, an optionally substituted diazole group, including amethyldiazole group, an optionally substituted triazole group, includinga methylsubstituted triazole group, a pyridine group, including a halo-(preferably, F) or methylsubstitutedpyridine group or an oxapyridinegroup (where the pyridine group is linked to the phenyl group by anoxygen) or an optionally substituted heterocycle (tetrahydrofuran,tetrahydrothiophene, pyrrolidine, piperidine, morpholine, piperazine,tetrahydroquinoline, oxane or thiane. Each of the aryl, heteroaryl orheterocyclic groups may be optionally connected to a PTM group(including a ULM′ group) via a linker group.

Preferred Heteroaryl groups for R^(3′) of ULM-g through ULM-i include anoptionally substituted quinoline (which may be attached to thepharmacophore or substituted on any carbon atom within the quinolinering), an optionally substituted indole (including dihydroindole), anoptionally substituted indolizine, an optionally substitutedazaindolizine (2, 3 or 4-azaindolizine) an optionally substitutedbenzimidazole, benzodiazole, benzoxofuran, an optionally substitutedimidazole, an optionally substituted isoxazole, an optionallysubstituted oxazole (preferably methyl substituted), an optionallysubstituted diazole, an optionally substituted triazole, a tetrazole, anoptionally substituted benzofuran, an optionally substituted thiophene,an optionally substituted thiazole (preferably methyl and/or thiolsubstituted), an optionally substituted isothiazole, an optionallysubstituted triazole (preferably a 1,2,3-triazole substituted with amethyl group, a triisopropylsilyl group, an optionally substituted—(CH₂)_(m)—O—C₁-C₆ alkyl group or an optionally substituted—(CH₂)_(m)—C(O)—O—C₁-C₆ alkyl group), an optionally substituted pyridine(2-, 3, or 4-pyridine) or a group according to the chemical structure:

wherein:

-   -   S^(c) of ULM-g through ULM-i is CHR^(SS), NR^(URE), or O ;    -   R^(HET) of ULM-g through ULM-i is H, CN, NO₂, halo (preferably        Cl or F), optionally substituted C₁-C₆ alkyl (preferably        substituted with one or two hydroxyl groups or up to three halo        groups (e.g. CF₃), optionally substituted O(C₁-C₆ alkyl)        (preferably substituted with one or two hydroxyl groups or up to        three halo groups) or an optionally substituted acetylenic group        —C≡C—R_(a) where R_(a) is H or a C₁-C₆ alkyl group (preferably        C₁-C₃ alkyl);    -   R^(SS) of ULM-g through ULM-i is H, CN, NO₂, halo (preferably F        or Cl), optionally substituted C₁-C₆ alkyl (preferably        substituted with one or two hydroxyl groups or up to three halo        groups), optionally substituted O—(C₁-C₆ alkyl) (preferably        substituted with one or two hydroxyl groups or up to three halo        groups) or an optionally substituted —C(O)(C₁-C₆alkyl)        (preferably substituted with one or two hydroxyl groups or up to        three halo groups);    -   R^(URE) of ULM-g through ULM-i is H, a C₁-C₆ alkyl (preferably H        or C₁-C₃ alkyl) or a —C(O)(C₁-C₆ alkyl), each of which groups is        optionally substituted with one or two hydroxyl groups or up to        three halogen, preferably fluorine groups, or an optionally        substituted heterocycle, for example piperidine, morpholine,        pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine,        piperazine, each of which is optionally substituted, and    -   Y^(C) of ULM-g through ULM-i is N or C—R^(YC), where R^(YC) is        H, OH, CN, NO₂, halo (preferably Cl or F), optionally        substituted C₁-C₆ alkyl (preferably substituted with one or two        hydroxyl groups or up to three halo groups (e.g. CF₃),        optionally substituted O(C₁-C₆ alkyl) (preferably substituted        with one or two hydroxyl groups or up to three halo groups) or        an optionally substituted acetylenic group —C≡C—R_(a) where        R_(a) is H or a C₁-C₆ alkyl group (preferably C₁-C₃ alkyl). Each        of said heteroaryl groups may be optionally connected to a PTM        group (including a ULM′ group) via a linker group.

Preferred heterocycle groups for R^(3′) of ULM-g through ULM-i includetetrahydroquinoline, piperidine, piperazine, pyrrollidine, morpholine,tetrahydrofuran, tetrahydrothiophene, oxane and thiane, each of whichgroups may be optionally substituted or a group according to thechemical structure:

preferably, a

group,wherein:

-   -   R^(PRO) of ULM-g through ULM-i is H, optionally substituted        C₁-C₆ alkyl or an optionally substituted aryl (phenyl or        napthyl), heteroaryl or heterocyclic group selected from the        group consisting of oxazole, isoxazole, thiazole, isothiazole,        imidazole, diazole, oximidazole, pyrrole, pyrollidine, furan,        dihydrofuran, tetrahydrofuran, thiene, dihydrothiene,        tetrahydrothiene, pyridine, piperidine, piperazine, morpholine,        quinoline, (each preferably substituted with a C₁-C₃ alkyl        group, preferably methyl or a halo group, preferably F or Cl),        benzofuran, indole, indolizine, azaindolizine;    -   R^(PRO1) and R^(PRO2) of ULM-g through ULM-i are each        independently H, an optionally substituted C₁-C₃ alkyl group or        together form a keto group, and    -   each n of ULM-g through ULM-i is 0, 1, 2, 3, 4, 5, or 6        (preferably 0 or 1), wherein each of said Heteocycle groups may        be optionally connected to a PTM group (including a ULM′ group)        via a linker group.

Preferred R^(3′) substituents of ULM-g through ULM-i also includespecifically (and without limitation to the specific compound disclosed)the R^(3′) substituents which are found in the identified compoundsdisclosed herein (which includes the specific compounds which aredisclosed in the present specification, and the figures which areattached hereto). Each of these R^(3′) substituents may be used inconjunction with any number of R^(2′) substituents, which are alsodisclosed herein.

In certain alternative preferred embodiments, R^(2′) of ULM-g throughULM-i is an optionally substituted —NR₁—X^(R2′)-alkyl group,—NR₁—X^(R2′)-Aryl group; an optionally substituted —NR₁—X^(R2′)-HET, anoptionally substituted —NR₁—X^(R2′)-Aryl-HET or an optionallysubstituted —NR₁—X^(R2′)-HET-Aryl,

wherein:

-   -   R₁ of ULM-g through ULM-i is H or a C₁-C₃ alkyl group        (preferably H);    -   X^(R2′) of ULM-g through ULM-i is an optionally substituted        —CH₂)_(n)—, —CH₂)_(n)—CH(X_(v))═CH(X_(v))— (cis or trans),        —(CH₂)_(n)—CH≡CH—, —(CH₂CH₂O)_(n)— or a C₃-C₆ cycloalkyl group;        and    -   X_(v) of ULM-g through ULM-i is H, a halo or a C₁-C₃ alkyl group        which is optionally substituted with one or two hydroxyl groups        or up to three halogen groups;    -   Alkyl of ULM-g through ULM-i is an optionally substituted C₁-C₁₀        alkyl (preferably a C₁-C₆ alkyl) group (in certain preferred        embodiments, the alkyl group is end-capped with a halo group,        often a Cl or Br);    -   Aryl of ULM-g through ULM-i is an optionally substituted phenyl        or naphthyl group (preferably, a phenyl group); and    -   HET of ULM-g through ULM-i is an optionally substituted oxazole,        isoxazole, thiazole, isothiazole, imidazole, diazole,        oximidazole, pyrrole, pyrollidine, furan, dihydrofuran,        tetrahydrofuran, thiene, dihydrothiene, tetrahydrothiene,        pyridine, piperidine, piperazine, morpholine, benzofuran,        indole, indolizine, azaindolizine, quinoline (when substituted,        each preferably substituted with a C₁-C₃ alkyl group, preferably        methyl or a halo group, preferably F or Cl) or a group according        to the chemical structure:

-   -   S^(c) of ULM-g through ULM-i is CHR^(SS), NR^(URE), or O ;    -   R^(HET) of ULM-g through ULM-i is H, CN, NO₂, halo (preferably        Cl or F), optionally substituted C₁-C₆ alkyl (preferably        substituted with one or two hydroxyl groups or up to three halo        groups (e.g. CF₃), optionally substituted O(C₁-C₆ alkyl)        (preferably substituted with one or two hydroxyl groups or up to        three halo groups) or an optionally substituted acetylenic group        —C≡C—R_(a) where R_(a) is H or a C₁-C₆ alkyl group (preferably        C₁-C₃ alkyl);    -   R^(SS) of ULM-g through ULM-i is H, CN, NO₂, halo (preferably F        or Cl), optionally substituted C₁-C₆ alkyl (preferably        substituted with one or two hydroxyl groups or up to three halo        groups), optionally substituted O—(C₁-C₆ alkyl) (preferably        substituted with one or two hydroxyl groups or up to three halo        groups) or an optionally substituted —C(O)(C₁-C₆alkyl)        (preferably substituted with one or two hydroxyl groups or up to        three halo groups);    -   R^(URE) of ULM-g through ULM-i is H, a C₁-C₆ alkyl (preferably H        or C₁-C₃ alkyl) or a —C(O)(C₁-C₆ alkyl), each of which groups is        optionally substituted with one or two hydroxyl groups or up to        three halogen, preferably fluorine groups, or an optionally        substituted heterocycle, for example piperidine, morpholine,        pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine,        piperazine, each of which is optionally substituted;    -   Y^(C) of ULM-g through ULM-i is N or C—R^(YC), where R^(YC) is        H, OH, CN, NO₂, halo (preferably Cl or F), optionally        substituted C₁-C₆ alkyl (preferably substituted with one or two        hydroxyl groups or up to three halo groups (e.g. CF₃),        optionally substituted O(C₁-C₆ alkyl) (preferably substituted        with one or two hydroxyl groups or up to three halo groups) or        an optionally substituted acetylenic group —C≡C—R_(a) where        R_(a) is H or a C₁-C₆ alkyl group (preferably C₁-C₃ alkyl);    -   R^(PRO) of ULM-g through ULM-i is H, optionally substituted        C₁-C₆ alkyl or an optionally substituted aryl (phenyl or        napthyl), heteroaryl or heterocyclic group selected from the        group consisting of oxazole, isoxazole, thiazole, isothiazole,        imidazole, diazole, oximidazole, pyrrole, pyrollidine, furan,        dihydrofuran, tetrahydrofuran, thiene, dihydrothiene,        tetrahydrothiene, pyridine, piperidine, piperazine, morpholine,        quinoline, (each preferably substituted with a C₁-C₃ alkyl        group, preferably methyl or a halo group, preferably F or Cl),        benzofuran, indole, indolizine, azaindolizine;    -   R^(PRO1) and R^(PRO2) of ULM-g through ULM-i are each        independently H, an optionally substituted C₁-C₃ alkyl group or        together form a keto group, and    -   each n of ULM-g through ULM-i is independently 0, 1, 2, 3, 4, 5,        or 6 (preferably 0 or 1).

Each of said groups may be optionally connected to a PTM group(including a ULM′ group) via a linker group.

In certain alternative preferred embodiments of the present invention,R^(3′) of ULM-g through ULM-i is an optionally substituted—(CH₂)_(n)—(V)_(n′)—(CH₂)_(n)—(V)_(n′)—R^(S3′)group, an optionallysubstituted-(CH₂)_(n)—N(R_(1′))(C═O)_(m′)—(V)_(n′)—R^(S3′) group, anoptionally substituted —X^(R3′)-alkyl group, an optionally substituted—X^(R3′)-Aryl group; an optionally substituted —X^(R3′)-HET group, anoptionally substituted —X^(R3′)-Aryl-HET group or an optionallysubstituted —X^(R3′)-HET-Aryl group,

wherein:

-   -   R^(S3′) is an optionally substituted alkyl group (C₁-C₁₀,        preferably C₁-C₆ alkyl), an optionally substituted Aryl group or        a HET group;    -   R_(1′) is H or a C₁-C₃ alkyl group (preferably H);    -   V is O, S or NR_(1′);    -   X^(R3′) is —(CH₂)_(n)—, —(CH₂CH₂O)_(n)—,        —CH₂)_(n)—CH(X_(v))═CH(X_(v))— (cis or trans), —CH₂)_(n)—CH—CH—,        or a C₃-C₆ cycloalkyl group, all optionally substituted;    -   X_(v) is H, a halo or a C₁-C₃ alkyl group which is optionally        substituted with one or two hydroxyl groups or up to three        halogen groups;    -   Alkyl is an optionally substituted C₁-C₁₀ alkyl (preferably a        C₁-C₆ alkyl) group (in certain preferred embodiments, the alkyl        group is end-capped with a halo group, often a Cl or Br);    -   Aryl is an optionally substituted phenyl or napthyl group        (preferably, a phenyl group); and    -   HET is an optionally substituted oxazole, isoxazole, thiazole,        isothiazole, imidazole, diazole, oximidazole, pyrrole,        pyrollidine, furan, dihydrofuran, tetrahydrofuran, thiene,        dihydrothiene, tetrahydrothiene, pyridine, piperidine,        piperazine, morpholine, benzofuran, indole, indolizine,        azaindolizine, quinoline (when substituted, each preferably        substituted with a C₁-C₃ alkyl group, preferably methyl or a        halo group, preferably F or Cl), or a group according to the        chemical structure:

-   -   S^(c) of ULM-g through ULM-i is CHR^(SS), NR^(URE), or O ;    -   R^(HET) of ULM-g through ULM-i is H, CN, NO₂, halo (preferably        Cl or F), optionally substituted C₁-C₆ alkyl (preferably        substituted with one or two hydroxyl groups or up to three halo        groups (e.g. CF₃), optionally substituted O(C₁-C₆ alkyl)        (preferably substituted with one or two hydroxyl groups or up to        three halo groups) or an optionally substituted acetylenic group        —C≡C—R_(a) where R_(a) is H or a C₁-C₆ alkyl group (preferably        C₁-C₃ alkyl);    -   R^(SS) of ULM-g through ULM-i is H, CN, NO₂, halo (preferably F        or Cl), optionally substituted C₁-C₆ alkyl (preferably        substituted with one or two hydroxyl groups or up to three halo        groups), optionally substituted O—(C₁-C₆ alkyl) (preferably        substituted with one or two hydroxyl groups or up to three halo        groups) or an optionally substituted —C(O)(C₁-C₆alkyl)        (preferably substituted with one or two hydroxyl groups or up to        three halo groups);    -   R^(URE) of ULM-g through ULM-i is H, a C₁-C₆ alkyl (preferably H        or C₁-C₃ alkyl) or a —C(O)(C₀-C₆ alkyl), each of which groups is        optionally substituted with one or two hydroxyl groups or up to        three halogen, preferably fluorine groups, or an optionally        substituted heterocycle, for example piperidine, morpholine,        pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine,        piperazine, each of which is optionally substituted;    -   Y^(C) of ULM-g through ULM-i is N or C—R^(YC), where R^(YC) is        H, OH, CN, NO₂, halo (preferably Cl or F), optionally        substituted C₁-C₆ alkyl (preferably substituted with one or two        hydroxyl groups or up to three halo groups (e.g. CF₃),        optionally substituted O(C₁-C₆ alkyl) (preferably substituted        with one or two hydroxyl groups or up to three halo groups) or        an optionally substituted acetylenic group —C≡C—R_(a) where        R_(a) is H or a C₁-C₆ alkyl group (preferably C₁-C₃ alkyl);    -   R^(PRO) of ULM-g through ULM-i is H, optionally substituted        C₁-C₆ alkyl or an optionally substituted aryl (phenyl or        napthyl), heteroaryl or heterocyclic group selected from the        group consisting of oxazole, isoxazole, thiazole, isothiazole,        imidazole, diazole, oximidazole, pyrrole, pyrollidine, furan,        dihydrofuran, tetrahydrofuran, thiene, dihydrothiene,        tetrahydrothiene, pyridine, piperidine, piperazine, morpholine,        quinoline, (each preferably substituted with a C₁-C₃ alkyl        group, preferably methyl or a halo group, preferably F or Cl),        benzofuran, indole, indolizine, azaindolizine;    -   R^(PRO1) and R^(PRO2) of ULM-g through ULM-i are each        independently H, an optionally substituted C₁-C₃ alkyl group or        together form a keto group;    -   each n of ULM-g through ULM-i is independently 0, 1, 2, 3, 4, 5,        or 6 (preferably 0 or 1);    -   each m′ of ULM-g through ULM-i is 0 or 1; and    -   each n′ of ULM-g through ULM-i is 0 or 1;    -   wherein each of said compounds, preferably on the alkyl, Aryl or        Het groups, is optionally connected to a PTM group (including a        ULM′ group) via a linker.

In alternative embodiments, R^(3′) of ULM-g through ULM-i is—(CH₂)_(n)-Aryl, —(CH₂CH₂O)_(n)-Aryl, —(CH₂)_(n)-HET or—(CH₂CH₂O)_(n)-HET,

wherein:

-   -   said Aryl of ULM-g through ULM-i is phenyl which is optionally        substituted with one or two substitutents, wherein said        substituent(s) is preferably selected from —(CH₂)_(n)OH, C₁-C₆        alkyl which itself is further optionally substituted with CN,        halo (up to three halo groups), OH, —(CH₂)_(n)O(C₁-C₆)alkyl,        amine, mono- or di-(C₁-C₆ alkyl) amine wherein the alkyl group        on the amine is optionally substituted with 1 or 2 hydroxyl        groups or up to three halo (preferably F, Cl) groups, or    -   said Aryl group of ULM-g through ULM-i is substituted with        —(CH₂)_(n)OH, —(CH₂)_(n)—O—(C₁-C₆)alkyl,        —(CH₂)_(n)—O—(CH₂)_(n)—(C₁-C₆)alkyl, —(CH₂)_(n)—C(O)(C₀-C₆)        alkyl, —(CH₂)_(n)—C(O)O(C₀-C₆)alkyl,        —(CH₂)_(n)—OC(O)(C₀-C₆)alkyl, amine, mono- or di-(C₁-C₆ alkyl)        amine wherein the alkyl group on the amine is optionally        substituted with 1 or 2 hydroxyl groups or up to three halo        (preferably F, Cl) groups, CN, NO₂, an optionally substituted        —(CH₂)_(n)—(V)_(m′)—CH₂)_(n)—(V)_(m′)—(C₁-C₆)alkyl group, a        —(V)_(m′)—(CH₂CH₂O)_(n)—R^(PEG) group where V is O, S or        NR_(1′), R_(1′) is H or a C₁-C₃ alkyl group (preferably H) and        R^(PEG) is H or a C₁-C₆ alkyl group which is optionally        substituted (including being optionally substituted with a        carboxyl group), or    -   said Aryl group of ULM-g through ULM-i is optionally substituted        with a heterocycle, including a heteroaryl, selected from the        group consisting of oxazole, isoxazole, thiazole, isothiazole,        imidazole, diazole, oximidazole, pyrrole, pyrollidine, furan,        dihydrofuran, tetrahydrofuran, thiene, dihydrothiene,        tetrahydrothiene, pyridine, piperidine, piperazine, morpholine,        quinoline, benzofuran, indole, indolizine, azaindolizine, (when        substituted each preferably substituted with a C₁-C₃ alkyl        group, preferably methyl or a halo group, preferably F or Cl),        or a group according to the chemical structure:

-   -   S^(c) of ULM-g through ULM-i is CHR^(SS), NR^(URE), or O ;    -   R^(HET) of ULM-g through ULM-i is H, CN, NO₂, halo (preferably        Cl or F), optionally substituted C₁-C₆ alkyl (preferably        substituted with one or two hydroxyl groups or up to three halo        groups (e.g. CF₃), optionally substituted O(C₁-C₆ alkyl)        (preferably substituted with one or two hydroxyl groups or up to        three halo groups) or an optionally substituted acetylenic group        —C≡C—R_(a) where R_(a) is H or a C₁-C₆ alkyl group (preferably        C₁-C₃ alkyl);    -   R^(SS) of ULM-g through ULM-i is H, CN, NO₂, halo (preferably F        or Cl), optionally substituted C₁-C₆ alkyl (preferably        substituted with one or two hydroxyl groups or up to three halo        groups), optionally substituted O—(C₁-C₆ alkyl) (preferably        substituted with one or two hydroxyl groups or up to three halo        groups) or an optionally substituted —C(O)(C₁-C₆alkyl)        (preferably substituted with one or two hydroxyl groups or up to        three halo groups);    -   R^(URE) of ULM-g through ULM-i is H, a C₁-C₆ alkyl (preferably H        or C₁-C₃ alkyl) or a —C(O)(C₀-C₆ alkyl), each of which groups is        optionally substituted with one or two hydroxyl groups or up to        three halogen, preferably fluorine groups, or an optionally        substituted heterocycle, for example piperidine, morpholine,        pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine,        piperazine, each of which is optionally substituted;    -   Y^(C) of ULM-g through ULM-i is N or C—R^(YC), where R^(YC) is        H, OH, CN, NO₂, halo (preferably Cl or F), optionally        substituted C₁-C₆ alkyl (preferably substituted with one or two        hydroxyl groups or up to three halo groups (e.g. CF₃),        optionally substituted O(C₁-C₆ alkyl) (preferably substituted        with one or two hydroxyl groups or up to three halo groups) or        an optionally substituted acetylenic group —C≡C—R_(a) where        R_(a) is H or a C₁-C₆ alkyl group (preferably C₁-C₃ alkyl);    -   R^(PRO) of ULM-g through ULM-i is H, optionally substituted        C₁-C₆ alkyl or an optionally substituted aryl (phenyl or        napthyl), heteroaryl or heterocyclic group selected from the        group consisting of oxazole, isoxazole, thiazole, isothiazole,        imidazole, diazole, oximidazole, pyrrole, pyrollidine, furan,        dihydrofuran, tetrahydrofuran, thiene, dihydrothiene,        tetrahydrothiene, pyridine, piperidine, piperazine, morpholine,        quinoline, (each preferably substituted with a C₁-C₃ alkyl        group, preferably methyl or a halo group, preferably F or Cl),        benzofuran, indole, indolizine, azaindolizine;    -   R^(PRO1) and R^(PRO2) of ULM-g through ULM-i are each        independently H, an optionally substituted C₁-C₃ alkyl group or        together form a keto group;    -   HET of ULM-g through ULM-i is preferably oxazole, isoxazole,        thiazole, isothiazole, imidazole, diazole, oximidazole, pyrrole,        pyrollidine, furan, dihydrofuran, tetrahydrofuran, thiene,        dihydrothiene, tetrahydrothiene, pyridine, piperidine,        piperazine, morpholine, quinoline, (each preferably substituted        with a C₁-C₃ alkyl group, preferably methyl or a halo group,        preferably F or Cl), benzofuran, indole, indolizine,        azaindolizine, or a group according to the chemical structure:

-   -   S^(c) of ULM-g through ULM-i is CHR^(SS), NR^(URE), or O ;    -   R^(HET) of ULM-g through ULM-i is H, CN, NO₂, halo (preferably        Cl or F), optionally substituted C₁-C₆ alkyl (preferably        substituted with one or two hydroxyl groups or up to three halo        groups (e.g. CF₃), optionally substituted O(C₁-C₆ alkyl)        (preferably substituted with one or two hydroxyl groups or up to        three halo groups) or an optionally substituted acetylenic group        —C≡C—R_(a) where R_(a) is H or a C₁-C₆ alkyl group (preferably        C₁-C₃ alkyl);    -   R^(SS) of ULM-g through ULM-i is H, CN, NO₂, halo (preferably F        or Cl), optionally substituted C₁-C₆ alkyl (preferably        substituted with one or two hydroxyl groups or up to three halo        groups), optionally substituted O—(C₁-C₆ alkyl) (preferably        substituted with one or two hydroxyl groups or up to three halo        groups) or an optionally substituted —C(O)(C₁-C₆alkyl)        (preferably substituted with one or two hydroxyl groups or up to        three halo groups);    -   R^(URE) of ULM-g through ULM-i is H, a C₁-C₆ alkyl (preferably H        or C₁-C₃ alkyl) or a —C(O)(C₀-C₆ alkyl), each of which groups is        optionally substituted with one or two hydroxyl groups or up to        three halogen, preferably fluorine groups, or an optionally        substituted heterocycle, for example piperidine, morpholine,        pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine,        piperazine, each of which is optionally substituted;    -   Y^(C) of ULM-g through ULM-i is N or C—R^(YC), where R^(YC) is        H, OH, CN, NO₂, halo (preferably Cl or F), optionally        substituted C₁-C₆ alkyl (preferably substituted with one or two        hydroxyl groups or up to three halo groups (e.g. CF₃),        optionally substituted O(C₁-C₆ alkyl) (preferably substituted        with one or two hydroxyl groups or up to three halo groups) or        an optionally substituted acetylenic group —C≡C—R_(a) where        R_(a) is H or a C₁-C₆ alkyl group (preferably C₁-C₃ alkyl);    -   R^(PRO) of ULM-g through ULM-i is H, optionally substituted        C₁-C₆ alkyl or an optionally substituted aryl, heteroaryl or        heterocyclic group;    -   R^(PRO1) and R^(PRO2) of ULM-g through ULM-i are each        independently H, an optionally substituted C₁-C₃ alkyl group or        together form a keto group;    -   each m′ of ULM-g through ULM-i is independently 0 or 1; and    -   each n of ULM-g through ULM-i is independently 0, 1, 2, 3, 4, 5,        or 6 (preferably 0 or 1), wherein each of said compounds,        preferably on said Aryl or HET groups, is optionally connected        to a PTM group (including a ULM′ group) via a linker group.

In still additional embodiments, preferred compounds include thoseaccording to the chemical structure:

wherein:

-   -   R^(1′) of ULM-i is OH or a group which is metabolized in a        patient or subject to OH;    -   R^(2′) of ULM-i is a —NH—CH₂-Aryl-HET (preferably, a phenyl        linked directly to a methyl substituted thiazole);    -   R^(3′) of ULM-i is a —CHR^(CR3′)—NH—C(O)—R^(3P1) group or a        —CHR^(CR3′)—R^(3P2) group;    -   R^(CR3′) of ULM-i is a C₁-C₄ alkyl group, preferably methyl,        isopropyl or tert-butyl;    -   R^(3P1) of ULM-i is C₁-C₃ alkyl (preferably methyl), an        optionally substituted oxetane group (preferably methyl        substituted, a —(CH₂)_(n)OCH₃ group where n is 1 or 2        (preferably 2), or a

group (the ethyl ether group is preferably meta-substituted on thephenyl moiety), a morpholino group (linked to the carbonyl at the 2- or3-position;

-   -   R^(3P2) of ULM-i is a

group;

-   -   Aryl of ULM-i is phenyl;    -   HET of ULM-i is an optionally substituted thiazole or        isothiazole; and    -   R^(HET) of ULM-i is H or a halo group (preferably H);    -   or a pharmaceutically acceptable salt, stereoisomer, solvate or        polymorph thereof, wherein each of said compounds is optionally        connected to a PTM group (including a ULM′ group) via a linker        group.

In certain aspects, bifunctional compounds comprising a ubiquitin E3ligase binding moiety (ULM), wherein ULM is a group according to thechemical structure:

wherein:each R₅ and R₆ of ULM-j is independently OH, SH, or optionallysubstituted alkyl or R_(S), R₆, and the carbon atom to which they areattached form a carbonyl;R₇ of ULM-j is H or optionally substituted alkyl;E of ULM-j is a bond, C═O, or C═S;G of ULM-j is a bond, optionally substituted alkyl, —COOH or C=J;

J of ULM-j is O or N—R₈;

R_(S) of ULM-j is H, CN, optionally substituted alkyl or optionallysubstituted alkoxy;M of ULM-j is optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted heterocyclic or

each R₉ and R₁₀ of ULM-j is independently H; optionally substitutedalkyl, optionally substituted cycloalkyl, optionally substitutedhydroxyalkyl, optionally substituted thioalkyl, a disulphide linked ULM,optionally substituted heteroaryl, or haloalkyl; or R₉, R₁₀, and thecarbon atom to which they are attached form an optionally substitutedcycloalkyl;R₁₁ of ULM-j is optionally substituted heterocyclic, optionallysubstituted alkoxy, optionally substituted heteroaryl, optionallysubstituted aryl, or

R₁₂ of ULM-j is H or optionally substituted alkyl;R₁₃ of ULM-j is H, optionally substituted alkyl, optionally substitutedalkylcarbonyl, optionally substituted (cycloalkyl)alkylcarbonyl,optionally substituted aralkylcarbonyl, optionally substitutedarylcarbonyl, optionally substituted (heterocyclyl)carbonyl, oroptionally substituted aralkyl; optionally substituted(oxoalkyl)carbamate,each R₁₄ of ULM-j is independently H, haloalkyl, optionally substitutedcycloalkyl, optionally substituted alkyl or optionally substitutedheterocycloalkyl;R₁₅ of ULM-j is H, optionally substituted heteroaryl, haloalkyl,optionally substituted aryl, optionally substituted alkoxy, oroptionally substituted heterocyclyl;each R₁₆ of ULM-j is independently halo, optionally substituted alkyl,optionally substituted haloalkyl, CN, or optionally substitutedhaloalkoxy;each R₂₅ of ULM-j is independently H or optionally substituted alkyl; orboth R₂₅ groups can be taken together to form an oxo or optionallysubstituted cycloalkyl group;

R₂₃ of ULM-j is H or OH;

Z₁, Z₂, Z₃, and Z₄ of ULM-j are independently C or N; ando of ULM-j is 0, 1, 2, 3, or 4, or a pharmaceutically acceptable salt,stereoisomer, solvate or polymorph thereof.

In certain embodiments, wherein G of ULM-j is C=J, J is O, R₇ is H, eachR₁₄ is H, and o is 0.

In certain embodiments, wherein G of ULM-j is C=J, J is O, R₇ is H, eachR₁₄ is H, R₁₅ is optionally substituted heteroaryl, and o is 0. In otherinstances, E is C═O and M is

In certain embodiments, wherein E of ULM-j is C═O, R₁₁ is optionallysubstituted heterocyclic or

and M is

In certain embodiments, wherein E of ULM-j is C═O, M is

and R₁₁ is

each R₁₈ is independently halo, optionally substituted alkoxy, cyano,optionally substituted alkyl, haloalkyl, or haloalkoxy; and p is 0, 1,2, 3, or 4.

In certain embodiments, ULM and where present, ULM′, are eachindependently a group according to the chemical structure:

wherein:

-   -   G of ULM-k is C=J, J is O;    -   R₇ of ULM-k is H;    -   each R₁₄ of ULM-k is H;    -   o of ULM-k is 0;

R₁₅ of ULM-k is

and

-   -   R₁₇ of ULM-k is H, halo, optionally substituted cycloalkyl,        optionally substituted alkyl, optionally substituted alkenyl,        and haloalkyl.

In other instances, R₁₇ of ULM-k is alkyl (e.g., methyl) or cycloalkyl(e.g., cyclopropyl).

In other embodiments, ULM and where present, ULM′, are eachindependently a group according to the chemical structure:

wherein:

-   -   G of ULM-k is C=J, J is O;    -   R₇ of ULM-k is H;    -   each R₁₄ of ULM-k is H;    -   o of ULM-k is 0; and    -   R₁₅ of ULM-k is selected from the group consisting of:

whereinR₃₀ of ULM-k is H or an optionally substituted alkyl.

In other embodiments, ULM and where present, ULM′, are eachindependently a group according to the chemical structure:

wherein:

-   -   E of ULM-k is C═O;    -   M of ULM-k is

and

-   -   R₁₁ of ULM-k is selected from the group consisting of:

In still other embodiments, a compound of the chemical structure,

wherein E of ULM-k is C═O;

R₁₁ of ULM-k is

and

M of ULM-k is

q of ULM-k is 1 or 2;

R₂₀ of ULM-k is H, optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted aryl, or

R₂₁ of ULM-k is H or optionally substituted alkyl; andR₂₂ of ULM-k is H, optionally substituted alkyl, optionally substitutedalkoxy, or haloalkyl.

In any embodiment described herein, R₁₁ of ULM-j or ULM-k is selectedfrom the group consisting of:

In certain embodiments, R₁₁ of ULM-j or ULM-k is selected from the groupconsisting of:

In certain embodiments, ULM (or when present ULM′) is a group accordingto the chemical structure:

wherein:

-   -   X of ULM-1 is O or S;    -   Y of ULM-1 is H, methyl or ethyl;    -   R₁₇ of ULM-1 is H, methyl, ethyl, hydoxymethyl or cyclopropyl;    -   M of ULM-1 is optionally substituted aryl, optionally        substituted heteroaryl, or

R⁹ of ULM-1 is H;

-   -   R₁₀ of ULM-1 is H, optionally substituted alkyl, optionally        substituted haloalkyl, optionally substituted heteroaryl,        optionally substituted aryl, optionally substituted        hydroxyalkyl, optionally substituted thioalkyl or cycloalkyl;    -   R11 of ULM-1 is optionally substituted heteroaromatic,        optionally substituted heterocyclic, optionally substituted aryl        or

-   -   R₁₂ of ULM-1 is H or optionally substituted alkyl; and    -   R₁₃ of ULM-1 is H, optionally substituted alkyl, optionally        substituted alkylcarbonyl, optionally substituted        (cycloalkyl)alkylcarbonyl, optionally substituted        aralkylcarbonyl, optionally substituted arylcarbonyl, optionally        substituted (heterocyclyl)carbonyl, or optionally substituted        aralkyl; optionally substituted (oxoalkyl)carbamate.

In some embodiments, ULM and where present, ULM′, are each independentlya group according to the chemical structure:

wherein:

-   -   Y of ULM-m is H, methyol or ethyl    -   R₉ of ULM-m is H;    -   R₁₀ is isopropyl, tert-butyl, sec-butyl, cyclopentyl, or        cyclohexyl;    -   R₁₁ of ULM-m is optionally substituted amide, optionally        substituted isoindolinone, optionally substituted isooxazole,        optionally substituted heterocycles.

In other preferred embodiments of the invention, ULM and where present,ULM′, are each independently a group according to the chemicalstructure:

Wherein:

-   -   R₁₇ of ULM-n is methyl, ethyl, or cyclopropyl; and    -   R₉, R₁₀, and R₁₁ of ULM-n are as defined above. In other        instances, R₉ is H; and    -   R₁₀ of ULM-n is H, alkyl, or or cycloalkyl (preferably,        isopropyl, tert-butyl, sec-butyl, cyclopentyl, or cyclohexyl).

In any of the aspects or embodiments described herein, the ULM (or whenpresent, ULM′) as described herein may be a pharmaceutically acceptablesalt, enantiomer, diastereomer, solvate or polymorph thereof. Inaddition, in any of the aspects or embodiments described herein, the ULM(or when present, ULM′) as described herein may be coupled to a PTMdirectly via a bond or by a chemical linker.

In certain aspects of the invention, the ULM moiety is selected from thegroup consisting of:

wherein the VLM may be connected to a PTM via a linker, as describedherein, at any appropriate location, including, e.g., an aryl,heteroary, phenyl, or phenyl of an indole group, optionally via anyappropriate functional group, such as an amine, ester, ether, alkyl, oralkoxy.

Exemplary Linkers

In certain embodiments, the compounds as described herein include one ormore PTMs chemically linked or coupled to one or more ULMs (e.g., atleast one of CLM, VLM, MLM, ILM, or a combination thereof) via achemical linker (L). In certain embodiments, the linker group L is agroup comprising one or more covalently connected structural units(e.g., -A^(L) ₁ . . . (A^(L))_(q)- or -(A^(L))_(q)-), wherein A₁ is agroup coupled to PTM, and (A^(L))_(q) is a group coupled to ULM.

In any aspect or embodiment described herein, the linker group L is abond or a chemical linker group represented by the formula-(A^(L))_(q)-, wherein A is a chemical moiety and q is an integer from1-100, and wherein L is covalently bound to the PTM and the ULM, andprovides for sufficient binding of the PTM to the protein target and theULM to an E3 ubiquitin ligase to result in target proteinubiquitination.

In certain embodiments, the linker group L is -(A^(L))_(q)-, wherein:

-   -   (A^(L))_(q) is a group which is connected to at least one of a        ULM moiety, a PTM moiety, or a combination thereof;    -   q of the linker is an integer greater than or equal to 1;    -   each A^(L) is independently selected from the group consisting        of, a bond, CR^(L1)R^(L2), O, S, SO, SO₂, NR^(L3), SO₂NR^(L3),        SONR^(L3), CONR^(L3), NR^(L3)CONR^(L4), NR^(L3)SO₂NR^(L4), CO,        CR^(L1)═CR^(L2), C≡C, SiR^(L1)R^(L2), P(O)R^(L1), P(O)OR^(L1),        NR^(L3)C(═NCN)NR^(L4), NR^(L3)C(═NCN), NR^(L3)C(═CNO₂)NR^(L4),        C₃₋₁₁cycloalkyl optionally substituted with 0-6 R^(L1) and/or        R^(L2) groups, C₅₋₁₃ spirocycloalkyl optionally substituted with        0-9 R^(L1) and/or R^(L2) groups, C₃₋₁₁ heterocyclyl optionally        substituted with 0-6 R^(L1) and/or R^(L2) groups, C₅₋₁₃        spiroheterocycloalkyl optionally substituted with 0-8 R^(L1)        and/or R^(L2) groups, aryl optionally substituted with 0-6        R^(L1) and/or R^(L2) groups, heteroaryl optionally substituted        with 0-6 R^(L1) and/or R^(L2) groups, where R^(L1) or R^(L2),        each independently are optionally linked to other groups to form        cycloalkyl and/or heterocyclyl moiety, optionally substituted        with 0-4 R¹″ groups; and    -   R^(L1), R^(L2), R^(L3), R^(L4) and R^(L5) are, each        independently, H, halo, C₁₋₈alkyl, OC₁₋₈alkyl, SC₁₋₈alkyl,        NHC₁₋₈alkyl, N(C₁₋₈alkyl)₂, C₃₋₁₁cycloalkyl, aryl, heteroaryl,        C₃₋₁₁heterocyclyl, OC₁₋₈cycloalkyl, SC₁₋₈cycloalkyl,        NHC₁₋₈cycloalkyl, N(C₁₋₈cycloalkyl)₂,        N(C₁₋₈cycloalkyl)(C₁₋₈alkyl), OH, NH₂, SH, SO₂C₁₋₈alkyl,        P(O)(OC₁₋₈alkyl)(C₁₋₈alkyl), P(O)(OC₁₋₈alkyl)₂, CC—C₁₋₈alkyl,        CCH, CH═CH(C₁₋₈alkyl), C(C₁₋₈alkyl)═CH(C₁₋₈alkyl),        C(C₁₋₈alkyl)═C(C₁₋₈alkyl)₂, Si(OH)₃, Si(C₁₋₈alkyl)₃,        Si(OH)(C₁₋₈alkyl)₂, COC₁₋₈alkyl, CO₂H, halogen, CN, CF₃, CHF₂,        CH₂F, NO₂, SF₅, SO₂NHC₁₋₈alkyl, SO₂N(C₁₋₈alkyl)₂, SONHC₁₋₈alkyl,        SON(C₁₋₈alkyl)₂, CONHC₁₋₈alkyl, CON(C₁₋₈alkyl)₂,        N(C₁₋₈alkyl)CONH(C₁₋₈alkyl), N(C₁₋₈alkyl)CON(C₁₋₈alkyl)₂,        NHCONH(C₁₋₈alkyl), NHCON(C₁₋₈alkyl)₂, NHCONH₂,        N(C₁₋₈alkyl)SO₂NH(C₁₋₈alkyl), N(C₁₋₈alkyl) SO₂N(C₁₋₈alkyl)₂, NH        SO₂NH(C₁₋₈alkyl), NH SO₂N(C₁₋₈alkyl)₂, NH SO₂NH₂.

In certain embodiments, q of the linker is an integer greater than orequal to 0. In certain embodiments, q is an integer greater than orequal to 1.

In certain embodiments, e.g., where q of the linker is greater than 2,(A^(L))_(q) is a group which is connected to ULM, and A_(L1) and(A^(L))_(q) are connected via structural units of the linker (L).

In certain embodiments, e.g., where q of the linker is 2, (A^(L))_(q) isa group which is connected to A^(L) ₁ and to a ULM.

In certain embodiments, e.g., where q of the linker is 1, the structureof the linker group L is -A^(L) ₁- , and A^(L) ₁ is a group which isconnected to a ULM moiety and a PTM moiety.

In certain embodiments, the linker (L) comprises a group represented bya general structure selected from the group consisting of:

—NR(CH₂)_(n)-(lower alkyl)-, —NR(CH₂)_(n)-(lower alkoxyl)-,—NR(CH₂)_(n)-(lower alkoxyl)-OCH₂—, —NR(CH₂)_(n)-(lower alkoxyl)-(loweralkyl)-OCH₂—, —NR(CH₂)_(n)-(cycloalkyl)-(lower alkyl)-OCH₂—,—NR(CH₂)_(n)-(hetero cycloalkyl)-, —NR(CH₂CH₂O)_(n)-(loweralkyl)-O—CH₂—, NR(CH₂CH₂O)_(n)-(hetero cycloalkyl)-O—CH₂—,—NR(CH₂CH₂O)_(n)-Aryl-O—CH₂—, —NR(CH₂CH₂O)_(n)-(hetero aryl)-O—CH₂—,—NR(CH₂CH₂O)_(n)-(cyclo alkyl)-O-(hetero aryl)-O—CH₂—,—NR(CH₂CH₂O)_(n)-(cyclo alkyl)-O-Aryl-O—CH₂—, —NR(CH₂CH₂O)_(n)-(loweralkyl)-NH-Aryl-O—CH₂—, NR(CH₂CH₂O)_(n)-(lower alkyl)-O-Aryl-CH₂,—NR(CH₂CH₂O)_(n)-cycloalkyl-O-Aryl-,—NR(CH₂CH₂O)_(n)-cycloalkyl-O-(hetero aryl)l-,—NR(CH₂CH₂)_(n)-(cycloalkyl)-O-(heterocycle)-CH₂,—NR(CH₂CH₂)_(n)-(heterocycle)-(heterocycle)-CH₂,—N(R1R2)-(heterocycle)-CH₂; where

n of the linker can be 0 to 10;

R of the linker can be H, lower alkyl;

R1 and R2 of the linker can form a ring with the connecting N.

In certain embodiments, the linker (L) comprises a group represented bya general structure selected from the group consisting of:

—N(R)—(CH2)_(m)—O(CH2)_(n)—O(CH2)_(o)—O(CH2)_(p)—O(CH2)_(q)—O(CH2)_(r)-OCH₂—,

—O—(CH2)_(m)—O(CH2)_(n)—O(CH2)_(o)—O(CH2)_(p)—O(CH2)_(q)—O(CH2)_(r)-OCH₂—,

—O—(CH2)_(m)—O(CH2)_(n)—O(CH2)_(o)—O(CH2)_(p)—O(CH2)_(q)—O(CH2)_(r)—O—;

—N(R)—(CH2)_(m)—O(CH2)_(n)—O(CH2)_(o)—O(CH2)_(p)—O(CH2)_(q)—O(CH2)_(r)—O—;

—(CH2)_(m)—O(CH2)_(n)—O(CH2)_(o)—O(CH2)_(p)—O(CH2)_(q)—O(CH2)_(r)—O—;

—(CH2)_(m)—O(CH2)_(n)—O(CH2)_(o)—O(CH2)_(p)—O(CH2)_(q)—O(CH2)_(r)-OCH₂—;

—(CH2)_(m)O(CH2)_(n)—O(CH2)_(o)—O(CH2)_(p)—O(CH2)_(q)—O(CH2)_(r)—O—;

—(CH2)_(m)—O(CH2)_(n)—O(CH2)_(o)—O(CH2)_(p)—O(CH2)_(q)—O(CH2)_(r)-OCH2;

wherein

m, n, o, p, q, and r of the linker are independently 0, 1, 2, 3, 4, 5,6;

when the number is zero, there is no N—O or O—O bond

R of the linker is H, methyl and ethyl;

X of the linker is H and F

where m of the linker can be 2, 3, 4, 5

where each n and m of the linker can independently be 0, 1, 2, 3, 4, 5,6.

In any aspect or embodiment described herein, the linker (L) is selectedfrom the group consisting of:

In any aspect or embodiment described herein, the linker (L) is selectedfrom the group consisting of:

wherein each m, n, o, p, q, r, and s is independently 0, 1, 2, 3, 4, 5,6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.

In any aspect or embodiment described herein, L is selected from thegroup consisting of:

In additional embodiments, the linker (L) comprises a structure selectedfrom, but not limited to the structure shown below, where a dashed lineindicates the attachment point to the PTM or ULM moieties.

wherein:

-   -   W^(L1) and W^(L2) are each independently a 4-8 membered ring        with 0-4 heteroatoms, optionally substituted with R^(Q), each        R^(Q) is independently a H, halo, OH, CN, CF₃, C₁-C₆ alkyl        (linear, branched, optionally substituted), C₁-C₆ alkoxy        (linear, branched, optionally substituted), or 2 R^(Q) groups        taken together with the atom they are attached to, form a 4-8        membered ring system containing 0-4 heteroatoms;    -   Y^(L1) is each independently a bond, C₁-C₆ alkyl (linear,        branched, optionally substituted) and optionally one or more C        atoms are replaced with O; or C₁-C₆ alkoxy (linear, branched,        optionally substituted);    -   n is 0-10; and    -   a dashed line indicates the attachment point to the PTM or ULM        moieties.

In additional embodiments, the linker (L) comprises a structure selectedfrom, but not limited to the structure shown below, where a dashed lineindicates the attachment point to the PTM or ULM moieties.

wherein:

-   -   W^(L1) and W^(L2) are each independently aryl, heteroaryl,        cyclic, heterocyclic, C₁₋₆ alkyl, bicyclic, biaryl,        biheteroaryl, or biheterocyclic, each optionally substituted        with R^(Q), each R^(Q) is independently a H, halo, OH, CN, CF₃,        hydroxyl, nitro, C≡CH, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁-C₆ alkyl        (linear, branched, optionally substituted), C₁-C₆ alkoxy        (linear, branched, optionally substituted), OC₁₋₃alkyl        (optionally substituted by 1 or more —F), OH, NH₂,        NR^(Y1)R^(Y2), CN, or 2 R^(Q) groups taken together with the        atom they are attached to, form a 4-8 membered ring system        containing 0-4 heteroatoms;    -   Y^(L1) is each independently a bond, NR^(YL1), O, S, NR^(YL2),        CR^(YL1)R^(YL2), C═O, C═S, SO, SO₂, C₁-C₆alkyl (linear,        branched, optionally substituted) and optionally one or more C        atoms are replaced with O; C₁-C₆ alkoxy (linear, branched,        optionally substituted);    -   Q^(L) is a 3-6 membered alicyclic or aromatic ring with 0-4        heteroatoms, optionally bridged, optionally substituted with 0-6        R^(Q), each R^(Q) is independently H, C₁₋₆ alkyl (linear,        branched, optionally substituted by 1 or more halo, C₁₋₆        alkoxyl), or 2 R^(Q) groups taken together with the atom they        are attached to, form a 3-8 membered ring system containing 0-2        heteroatoms);    -   R^(YL1), R^(YL2) are each independently H, OH, C₁₋₆ alkyl        (linear, branched, optionally substituted by 1 or more halo,        C₁₋₆ alkoxyl), or R¹, R² together with the atom they are        attached to, form a 3-8 membered ring system containing 0-2        heteroatoms);    -   n is 0-10; and    -   a dashed line indicates the attachment point to the PTM or ULM        moieties.

In additional embodiments, the linker group is optionally substituted(poly)ethyleneglycol having between 1 and about 100 ethylene glycolunits (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17,18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35,36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, etc.,ethylene glycol units), between about 1 and about 50 ethylene glycolunits, between 1 and about 25 ethylene glycol units, between about 1 and10 ethylene glycol units, between 1 and about 8 ethylene glycol unitsand 1 and 6 ethylene glycol units, between 2 and 4 ethylene glycolunits, or optionally substituted alkyl groups interdispersed withoptionally substituted, O, N, S, P or Si atoms. In certain embodiments,the linker is substituted with an aryl, phenyl, benzyl, alkyl, alkylene,or heterocycle group. In certain embodiments, the linker may beasymmetric or symmetrical.

In any of the embodiments of the compounds described herein, the linkergroup may be any suitable moiety as described herein. In one embodiment,the linker is a substituted or unsubstituted polyethylene glycol groupranging in size from about 1 to about 12 ethylene glycol units, between1 and about 10 ethylene glycol units, about 2 about 6 ethylene glycolunits, between about 2 and 5 ethylene glycol units, between about 2 and4 ethylene glycol units.

In any aspect or embodiment described herein, the linker (L) includesabout 1 to about 50 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13,14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31,32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49,or 50) alkylene glycol units that are optionally substituted, whereincarbon or oxygen may be substituted with a heteroatom selected from N,S, P, or Si atoms with an appropriate number of hydrogens to completevalency. For example, in any aspect or embodiment described herein, thelinker (L) has a chemical structure selected from:

wherein carbon or oxygen may be substituted with a heteroatom selectedfrom N, S, P, or Si atoms with an appropriate number of hydrogens tocomplete valency.

In another embodiment, the present disclosure is directed to a compoundwhich comprises a PTM group as described above, which binds to a targetprotein (e.g., IRAK-4) or polypeptide, which is ubiquitinated by anubiquitin ligase and is chemically linked directly to the ULM group orthrough a linker moiety L, or PTM is alternatively a ULM′ group which isalso an ubiquitin ligase binding moiety, which may be the same ordifferent than the ULM group as described above and is linked directlyto the ULM group directly or through the linker moiety; and L is alinker moiety as described above which may be present or absent andwhich chemically (covalently) links ULM to PTM, or a pharmaceuticallyacceptable salt, enantiomer, stereoisomer, solvate or polymorph thereof.

In certain embodiments, the linker group L is a group comprising one ormore covalently connected structural units independently selected fromthe group consisting of:

The X is selected from the group consisting of O, N, S, S(O) and SO₂; nis integer from 1-5, 5;R^(L1) is hydrogen or alkyl,

is a mono- or bicyclic aryl or heteroaryl optionally substituted with1-3 substituents selected from alkyl, halogen, haloalkyl, hydroxy,alkoxy or cyano;

is a mono- or bicyclic cycloalkyl or a heterocycloalkyl optionallysubstituted with 1-3 substituents selected from alkyl, halogen,haloalkyl, hydroxy, alkoxy or cyano; and the phenyl ring fragment can beoptionally substituted with 1, 2 or 3 substituents selected from thegroup consisting of alkyl, halogen, haloalkyl, hydroxy, alkoxy andcyano. In an embodiment, the linker group L comprises up to 10covalently connected structural units, as described above.

Although the ULM group and PTM group may be covalently linked to thelinker group through any group which is appropriate and stable to thechemistry of the linker, in preferred aspects of the present disclosure,the linker is independently covalently bonded to the ULM group and thePTM group preferably through an amide, ester, thioester, keto group,carbamate (urethane), carbon or ether, each of which groups may beinserted anywhere on the ULM group and PTM group to provide maximumbinding of the ULM group on the ubiquitin ligase and the PTM group onthe target protein to be degraded. (It is noted that in certain aspectswhere the PTM group is a ULM group, the target protein for degradationmay be the ubiquitin ligase itself). In certain preferred aspects, thelinker may be linked to an optionally substituted alkyl, alkylene,alkene or alkyne group, an aryl group or a heterocyclic group on the ULMand/or PTM groups.

Exemplary PTMs

In preferred aspects of the disclosure, the PTM group is a group, whichbinds to target proteins. Targets of the PTM group are numerous in kindand are selected from proteins that are expressed in a cell such that atleast a portion of the sequences is found in the cell and may bind to aPTM group. The term “protein” includes oligopeptides and polypeptidesequences of sufficient length that they can bind to a PTM groupaccording to the present disclosure. Any protein in a eukaryotic systemor a microbial system, including a virus, bacteria or fungus, asotherwise described herein, are targets for ubiquitination mediated bythe compounds according to the present disclosure. Preferably, thetarget protein is a eukaryotic protein.

PTM groups according to the present disclosure include, for example, anymoiety which binds to IRAK-4 specifically (binds to a target protein).The compositions described below exemplify some of the members of smallmolecule target protein binding moieties. Such small molecule targetprotein binding moieties also include pharmaceutically acceptable salts,enantiomers, solvates and polymorphs of these compositions, as well asother small molecules that may target a protein of interest. Thesebinding moieties are linked to the ubiquitin ligase binding moietypreferably through a linker in order to present a target protein (towhich the protein target moiety is bound) in proximity to the ubiquitinligase for ubiquitination and degradation.

The present disclosure may be used to treat a number of disease statesand/or conditions, including any disease state and/or condition in whichIRAK-4 is dysregulated and where a patient would benefit from thedegradation or inhibition of IRAK-4.

In an additional aspect, the description provides therapeuticcompositions comprising an effective amount of a compound as describedherein or salt form thereof, and a pharmaceutically acceptable carrier,additive or excipient, and optionally an additional bioactive agent. Thetherapeutic compositions modulate protein degradation in a patient orsubject, for example, an animal such as a human, and can be used fortreating or ameliorating disease states or conditions which aremodulated through the degraded protein. In certain embodiments, thetherapeutic compositions as described herein may be used to effectuatethe degradation of proteins of interest for the treatment oramelioration of a disease, e.g., cancer, inflammatorydiseases/disorders, autoimmune diseases/disorders, neurodegenerativediseases, and/or cardiovascular diseases/disorders.

In alternative aspects, the present disclosure relates to a method fortreating a disease state or ameliorating the symptoms of a disease orcondition in a subject in need thereof by degrading a protein orpolypeptide through which a disease state or condition is modulatedcomprising administering to said patient or subject an effective amount,e.g., a therapeutically effective amount, of at least one compound asdescribed hereinabove, optionally in combination with a pharmaceuticallyacceptable carrier, additive or excipient, and optionally an additionalbioactive agent, wherein the composition is effective for treating orameliorating the disease or disorder or symptom thereof in the subject.The method according to the present disclosure may be used to treat alarge number of disease states or conditions including cancer,inflammatory diseases/disorders, autoimmune diseases/disorders,neurodegenerative diseases, as well as cardiovasculardiseases/disorders, by virtue of the administration of effective amountsof at least one compound described herein. The disease state orcondition may be a disease caused by a microbial agent or otherexogenous agent such as a virus, bacteria, fungus, protozoa or othermicrobe or may be a disease state, which is caused by overexpression ofa protein, which leads to a disease state and/or condition.

In another aspect, the description provides methods for identifying theeffects of the degradation of proteins of interest in a biologicalsystem using compounds according to the present disclosure.

The term “target protein” is used to describe a protein or polypeptide,which is a target for binding to a compound according to the presentdisclosure and degradation by ubiquitin ligase hereunder. Such smallmolecule target protein binding moieties also include pharmaceuticallyacceptable salts, enantiomers, solvates and polymorphs of thesecompositions, as well as other small molecules that may target a proteinof interest. These binding moieties are linked to at least one ULM group(e.g. VLM, CLM, ILM, and/or MLM) through at least one linker group L.

Target proteins, which may be bound to the protein target moiety anddegraded by the ligase to which the ubiquitin ligase binding moiety isbound, include IRAK-4, including fragments thereof, analogues thereof,and/or homologues thereof.

These various protein targets may be used in screens that identifycompound moieties which bind to the protein and by incorporation of themoiety into compounds according to the present disclosure, the level ofactivity of the protein may be altered for therapeutic end result.

The term “protein target moiety” or PTM is used to describe a smallmolecule which binds to a target protein or other protein or polypeptideof interest and places/presents that protein or polypeptide in proximityto an ubiquitin ligase such that degradation of the protein orpolypeptide by ubiquitin ligase may occur. Non-limiting examples ofsmall molecule target protein binding moieties include IRAK-4, amongnumerous others. The compositions described below exemplify some of themembers of the small molecule target proteins.

The compositions described below exemplify some of the members of thesetypes of small molecule target protein binding moieties. Such smallmolecule target protein binding moieties also include pharmaceuticallyacceptable salts, enantiomers, solvates and polymorphs of thesecompositions, as well as other small molecules that may target a proteinof interest. References which are cited herein below are incorporated byreference herein in their entirety.

In any aspect or embodiment described herein, the PTM is represented byFormula PTM-I (which correspond to Formula I from U.S. PatentApplication Publication No. 2014/0329799 A1, which is incorporatedherein in its entirety for all purposes):

wherein:

-   -   X of PTM-I is —N═ or —CH═;    -   Y of PTM-I is selected from the group consisting of —NR²-, —CH₂—        and —O—; or when Y is —NR²—, R² and R³ together with the        nitrogen to which they are attached optionally form a 4- to        6-membered heterocyclic ring, wherein the 4- to 6-membered        heterocyclic ring is optionally substituted with 1 to 3        substituents independently selected from R⁷ groups;    -   R¹ of PTM-I is selected from the group consisting of: hydrogen,        C₁₋₁₀ alkyl, C₃₋₈ cycloalkyl, aryl, heterocyclyl, halogen,        —COOR⁷, —NR⁷, —SR⁷, —OR⁷, —SO₂R⁷, —COR⁷, —NCOR⁷, and —CONR⁷;    -   R² of PTM-I is selected from the group consisting of: hydrogen,        C₁₋₁₀ alkyl, and C₃₋₄ cycloalkyl;    -   R³ of PTM-I is selected from the group consisting of: hydrogen,        C₁₋₁₀ alkyl, C₃₋₄ cycloalkyl, aryl, heterocyclyl, and —COOR⁷;    -   R⁶ of PTM-I is selected from the group consisting of: C₁₋₁₀        alkyl, C₃₋₄ cycloalkyl, aryl, heterocyclyl, —COOR⁷, —SO₂R⁷,        —COR⁷; and    -   R⁷ of PTM-I is selected from the group consisting of: hydrogen,        C₁₋₁₀ alkyl, C₃₋₄ cycloalkyl, aryl, and heteroaryl;    -   wherein each of the C₁₋₁₀ alkyl, C₃₋₄ cycloalkyl, aryl and        heterocyclyl of R¹, R³, R⁶ and R⁷ is optionally substituted with        1-4 substituents independently selected from the group        consisting of C₁₋₄ alkyl, C₁₋₄ alkoxy, halogen, —SO₂R and —OR⁸;    -   R⁸ of PTM-I is selected from the group consisting of hydrogen,        and C₁₋₆ alkyl; and    -   the PTM-I is covalently joined to a ULM, a chemical linker group        (L), a CLM, an ILM, a VLM, MLM, a ULM′, a CLM′, a ILM′, a VLM′,        a MLM′, or combination thereof.

In any aspect or embodiment described herein, the PTM-I is covalentlyjoined to a ULM, a chemical linker group (L), a CLM, an ILM, a VLM, MLM,a ULM′, a CLM′, a ILM′, a VLM′, a MLM′, or combination thereof via an Rgroup (e.g., R¹, R², R³, R⁴, R⁵, R⁶, R⁷, or R⁸).

In any aspect or embodiment described herein, PTM-I may comprise:

-   -   X of PTM-I is —N═;    -   Y of PTM-I is —NH—;    -   R¹ of PTM-I is selected from the group consisting of: C₁₋₆        alkyl, C₃₋₆ cycloalkyl, aryl, and heterocyclyl;    -   R² of PTM-I is selected from the group consisting of: hydrogen,        and C₁₋₄ alkyl;    -   R³ of PTM-I is selected from the group consisting of: hydrogen,        C₁₋₆ alkyl, C₃₋₆ cycloalkyl, aryl, and heterocyclyl;    -   R⁶ of PTM-I is selected from the group consisting of: C₁₋₆        alkyl, C₃₋₆ cycloalkyl, aryl, and heterocyclyl; and    -   R⁷ of PTM-I is selected from the group consisting of: hydrogen,        C₁₋₆ alkyl, C₃₋₆ cycloalkyl, aryl, and heteroaryl;    -   wherein each of the C₁₋₆ alkyl, C₃₋₆ cycloalkyl, aryl and        heterocyclyl of R¹, R³, R⁶ and R⁷ is optionally substituted with        1-3 substituents independently selected from the group        consisting of C₁₋₄ alkyl, C₁₋₄ alkoxy, halogen, —SO₂R⁸ and —OR⁸;        and    -   R⁸ of PTM-I is selected from the group consisting of hydrogen,        methyl, and ethyl.

In any aspect or embodiment described herein, PTM-I may comprise:

-   -   X of PTM-I is —N═;    -   Y of PTM-I is —NH—;    -   R¹ of PTM-I is selected from the group consisting of: C₁₋₆        alkyl, C₃₋₆ cycloalkyl, aryl, and heterocyclyl;    -   R² of PTM-I is selected from the group consisting of: hydrogen,        and C₁₋₄ alkyl;    -   R³ of PTM-I is selected from the group consisting of: hydrogen,        C₁₋₆ alkyl, C₃₋₆ cycloalkyl, aryl, and heterocyclyl;    -   R⁶ of PTM-I is selected from the group consisting of: C₁₋₆        alkyl, C₃₋₆ cycloalkyl, aryl, and heterocyclyl; and    -   R⁷ of PTM-I is selected from the group consisting of: hydrogen,        C₁₋₆ alkyl, C₃₋₆ cycloalkyl, aryl, and heteroaryl;    -   wherein each of the C₁₋₆ alkyl, C₃₋₆ cycloalkyl, aryl and        heterocyclyl of R¹, R³, R⁶ and R⁷ of PTM-I is optionally        substituted with 1-3 substituents independently selected from        the group consisting of C₁₋₄ alkyl, C₁₋₄ alkoxy, oxo, halogen,        —SO₂R⁸ and —OR⁸; and    -   R⁸ of PTM-I is selected from the group consisting of hydrogen,        methyl, and ethyl.

In any aspect or embodiment described herein, R¹ of PTM-I is phenyl orheterocyclyl. For example, R¹ of PTM-I is selected from the groupconsisting of phenyl, pyridinyl, pyrimidinyl,

wherein each of the foregoing R¹ group is optionally substituted with1-3 substituents independently selected from methyl, ethyl, propyl,hydroxy, halogen, methoxy, ethoxy, oxo, phenyl optionally substitutedwith 1 or 2 groups independently selected from methyl and halogen.

In any aspect or embodiment described herein, R³ of PTM-I is C₁₋₆ alkyl,C₃₋₆ cycloalkyl, aryl, a 4-7 membered mono-cyclic ring containing 1-3hetero atoms selected from O, N and S, heteroaryl; wherein each of theforegoing R³ group is optionally substituted with 1-3 substituentsindependently selected from methyl, ethyl, propyl, hydroxy, halogen,methoxy, ethoxy, oxo, —SO₂-methyl, heteroaryl and phenyl optionallysubstituted with 1 or 2 groups independently selected from methyl andhalogen.

In any aspect or embodiment described herein, R³ of PTM-I is selectedfrom the group consisting of methyl, ethyl, propyl, butyl, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyridinyl, pyrimidinyl,

wherein each of the foregoing R³ group is optionally substituted with1-3 substituents independently selected from methyl, ethyl, propyl,hydroxy, halogen, methoxy, ethoxy, oxo, —SO₂-methyl, heteroaryl andphenyl optionally substituted with 1 or 2 groups independently selectedfrom methyl and halogen.

In any aspect or embodiment described herein, R⁶ of PTM-I is selectedfrom the group consisting of C₁₋₆ alkyl, C₃₋₆ cycloalkyl, aryl andheteroaryl; wherein each of the foregoing R⁶ group is optionallysubstituted with 1-3 substituents independently selected from methyl,ethyl, propyl, hydroxy, halogen, methoxy, ethoxy, oxo, —SO₂-methyl,heteroaryl and phenyl optionally substituted with 1 or 2 groupsindependently selected from methyl and halogen.

In any aspect or embodiment described herein, R⁶ of PTM-I is selectedfrom the group consisting of methyl, ethyl, propyl, butyl, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyridinyl, pyrimidinyl,

wherein each of the foregoing R⁶ group is optionally substituted with1-3 substituents independently selected from methyl, ethyl, propyl,hydroxy, halogen, methoxy, ethoxy, oxo, —SO₂-methyl, heteroaryl andphenyl optionally substituted with 1 or 2 groups independently selectedfrom methyl and halogen.

In any aspect or embodiment described herein, R⁶ of PTM-I is selectedfrom the group consisting of cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, phenyl, pyridinyl, pyrimidinyl,

wherein each of the foregoing R⁶ group is optionally substituted with1-3 substituents independently selected from methyl, ethyl, propyl,hydroxy, halogen, methoxy, ethoxy, oxo, heteroaryl and phenyl optionallysubstituted with 1 or 2 groups independently selected from methyl andhalogen.

In any aspect or embodiment described herein, the PTM of PTM-I isselected from the group consisting of(R)-2-(2-morpholino-6-oxo-4-(piperidin-3-ylamino)-1,6-dihydropyrimidin-5-yl)benzo[d]thiazole-5-carbonitrile(PTM-I-1),(R)-5-(benzo[d]thiazol-2-yl)-2-morpholino-6-(piperidin-3-ylamino)pyrimidin-4(3H)-one(PTM-I-2),6-(((1R,2S,3R,4R)-2,3-dihydroxy-4-(hydroxymethyl)cyclopentyl)amino)-5-(4-(4-fluorophenyl)thiazol-2-yl)-2-morpholinopyrimidin-4(3H)-one(PTM-I-3),(R)-5-(benzo[d]thiazol-2-yl)-2-(4-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)-6-(piperidin-3-ylamino)pyrimidin-4(3H)-one(PTM-I-4),5-(benzo[d]thiazol-2-yl)-6-(((1R,2S,3R,4R)-2,3-dihydroxy-4-(hydroxymethyl)cyclopentyl)amino)-2-(4-(pyridin-3-yl)piperazin-1-yl)pyrimidin-4(3H)-one(PTM-I-5),5-(benzo[d]thiazol-2-yl)-6-(((1R,2S,3R,4R)-2,3-dihydroxy-4-(hydroxymethyl)cyclopentyl)amino)-2-(4-(pyrimidin-5-yl)piperidin-1-yl)pyrimidin-4(3H)-one(PTM-I-6),(R)-5-(benzo[d]thiazol-2-yl)-6-(piperidin-3-ylamino)-2-(4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)pyrimidin-4(3H)-one(PTM-I-7,8-(5-(benzo[d]thiazol-2-yl)-4-(((1R,2S,3R,4R)-2,3-dihydroxy-4-(hydroxymethyl)cyclopentyl)amino)-6-oxo-1,6-dihydropyrimidin-2-yl)-2-methyl-2,8-diazaspiro[4.5]decan-1-one(PTM-I-8), and(R)-5-(benzo[d]thiazol-2-yl)-2-(4-(4-chloropyridin-2-yl)piperazin-1-yl)-6-(piperidin-3-ylamino)pyrimidin-4(3H)-one(PTM-1-9).

In any aspect or embodiment described herein, the PTM is represented byFormula PTM-II (which correspond to Formula I from U.S. PatentApplication Publication No. 2014/0194404 A1, which is incorporatedherein in its entirety for all purposes):

wherein:

-   -   R¹ of PTM-II is aryl, heteroaryl, heterocyclyl or (C₁₋₆        alkyl)R⁶, wherein said aryl, heteroaryl, and heterocyclyl groups        are optionally substituted with one or two substituents selected        from the group consisting of halo, cyano, R⁴, C₁₋₃ aminoalkyl,        C₁₋₃ hydroxyalkyl, C₃₋₄ cycloalkyl, OR⁴, NR⁴R⁵, NR⁴COR⁶,        NR⁴SO₂R⁶, SO₂NR⁴R⁵, CONR⁴R⁵;    -   R² of PTM-II of PTM-II is aryl, heteroaryl, C₃₋₈ cycloalkyl,        heterocyclyl or (C₁₋₆ alkyl)R⁶, wherein said aryl, heteroaryl,        cycloalkyl and heterocyclyl groups are optionally substituted        with one or two substituents selected from the group consisting        of halo, cyano, oxo, hydroxyl, imino, hydroxyimino, R⁴, OR⁴,        O(C₃₋₈ cycloalkyl), (C═O)OR⁴, SO_(m)R⁶, SO_(m)R⁴, NR⁴R⁵,        SO₂NR⁴R⁵ and NR⁴SO₂R⁶;    -   R³ of PTM-II is a halo, cyano, oxo, hydroxyl, imino,        hydroxyimino, R⁴, OR⁴, C₃₋₈ cycloalkyl, SO_(m)R⁶, SO_(m)R⁴NR⁴R⁵,        or (C═O)NR⁴R⁵, NR⁴(CO)R⁶, SO_(m)NR⁴R⁵ and NR⁴SO₂R⁶;    -   R⁴ of PTM-II is independently hydrogen or C₁₋₆ alkyl, wherein        said alkyl is optionally substituted with one to three halo or        hydroxyl;    -   R⁵ of PTM-II is independently hydrogen or C₁₋₆ alkyl, wherein        said alkyl is optionally substituted with halo or hydroxyl;    -   R⁶ of PTM-II is independently aryl, heteroaryl, C₃₋₈ cycloalkyl        or heterocyclyl;    -   m of PTM-II is an integer from zero to two; and    -   the PTM-II is covalently joined to a ULM, a chemical linker        group (L), a CLM, an ILM, a VLM, MLM, a ULM′, a CLM′, a ILM′, a        VLM′, a MLM′, or combination thereof.

In any aspect or embodiment described herein, the PTM-II is covalentlyjoined to a ULM, a chemical linker group (L), a CLM, an ILM, a VLM, MLM,a ULM′, a CLM′, a ILM′, a VLM′, a MLM′, or combination thereof via an Rgroup (e.g., R¹, R², R³, R⁴, R⁵, or R⁶).

In any aspect or embodiment described herein, R¹ of PTM-II is an aryl,wherein said aryl group is optionally substituted with one or twosubstituents selected from the group consisting of halo, cyano, R⁴, C₃₋₈cycloalkyl, C₁₋₃ aminoalkyl, C₁₋₃ hydroxyalkyl, OR⁴, NR⁴R⁵, NR⁴COR⁶,NR⁴SO₂R⁶, SO₂NR⁴R⁵, CONR⁴R⁵ and CONR⁴R⁵. In a subclass of the invention,R¹ is aryl, wherein said aryl group is optionally substituted with R⁴ orOR⁴. In a further subclass of the invention, R¹ is phenyl, wherein saidphenyl group is optionally substituted with R⁴ or OR⁴.

In any aspect or embodiment described herein, R² of PTM-II is aheteroaryl, wherein said heteroaryl group is optionally substituted withone or two substituents selected from the group consisting of halo,cyano, oxo, hydroxyl, imino, hydroxyimino, R⁴, OR⁴, O(C₃₋₈ cycloalkyl),(C═O)OR⁴, SO_(m)R⁶, SO_(m)R⁴, NR⁴R⁵, SO₂NR⁴R⁵ and NR⁴SO₂R⁶. In asubclass of the invention, R² is heteroaryl, wherein said heteroarylgroup is optionally substituted with one or two substituents selectedfrom the group consisting of halo, cyano, oxo, hydroxyl, imino,hydroxyimino, R⁴, OR⁴, O(C₃₋₈ cycloalkyl), (C═O)OR⁴, SO_(m)R⁶, SO_(m)R⁴,NR⁴R⁵, SO₂NR⁴R⁵ and NR⁴SO₂R⁶.

In any aspect or embodiment described herein, the PTM of PTM-II isselected from the group consisting of:N-(3-(4-oxocyclohexyl)-1-(p-tolyl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-1);N-(3-(4-(hydroxyimino)cyclohexyl)-1-(p-tolyl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-2);N-(3-(4-(methoxyimino)cyclohexyl)-1-(p-tolyl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-3);N-(3-(7-oxoazepan-4-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-4);N-(3-(4-(dimethylamino)cyclohexyl)-1-(p-tolyl)-1,4-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-5);N-(3-(4-hydroxycyclohexyl)-1-(p-tolyl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-6);N-(3-(piperidin-4-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-7);N-(1-(4-methoxyphenyl)-3-(piperidin-4-yl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-8);N-(1-(4-chlorophenyl)-3-(piperidin-4-yl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-9);N-(1-(4-fluorophenyl)-3-(piperidin-4-yl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-10);N-(3-(piperidin-4-yl)-1-(4-(trifluoromethyl)phenyl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-11);N-(1-(4-cyanophenyl)-3-(piperidin-4-yl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-12);N-(3-(piperidin-4-yl)-1-(4-(trifluoromethoxy)phenyl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-13);N-(3-(piperidin-4-yl)-1-(o-tolyl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-14);N-(3-(piperidin-4-yl)-1-(m-tolyl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-15);N-(1-(4-methoxyphenyl)-3-(1-(methylsulfonyl)piperidin-4-yl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-16);N-(3-(1-(methylsulfonyl)piperidin-4-yl)-1-(m-tolyl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-17);N-(3-(1-(methylsulfonyl)piperidin-4-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-18);N-(3-(1-(cyclopropylsulfonyl)piperidin-4-yl)-1-(4-(trifluoromethoxy)phenyl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-19);N-(3-(1-(methylsulfonyl)piperidin-4-yl)-1-phenyl-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-20);N-(3-(1-(cyclopropylsulfonyl)piperidin-4-yl)-1-(m-tolyl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-21);N-(3-(1-(cyclopropylsulfonyl)piperidin-4-yl)-1-(4-fluorophenyl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-22);N-(3-(1-(isopropylsulfonyl)piperidin-4-yl)-1-(4-methoxyphenyl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-23);N-(3-(1-(cyclopropylsulfonyl)piperidin-4-yl)-1-(4-methoxyphenyl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-24);N-(3-(1-(cyclopentylsulfonyl)piperidin-4-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-25);N-(3-(1-(cyclopropylsulfonyl)piperidin-4-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-26);N-(3-(1-(cyclopropylsulfonyl)piperidin-4-yl)-1-(4-(trifluoromethoxy)phenyl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-27);N-(1-(2,4-difluorophenyl)-3-(4-(N-methylsulfamoyl)phenyl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-28);N-(1-(4-chloro-2-fluorophenyl)-3-(1-(methylsulfonyl)piperidin-4-yl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-29);N-(1-(4-methoxyphenyl)-3-(1-((trifluoromethyl)sulfonyl)piperidin-4-yl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-30);N-(3-(1-acetylpiperidin-4-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-31); methyl4-(1-(4-methoxyphenyl)-5-(pyrazolo[1,5-a]pyrimidine-3-carboxamido)-1H-pyrazol-3-yl)piperidine-1-carboxylate(PTM-II-32);N-(3-(1-(cyclopropanecarbonyl)piperidin-4-yl)-1-(4-methoxyphenyl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-33);N-(1-(2,4-difluorophenyl)-3-(4-(N-methylsulfamoyl)phenyl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-34);N-(3-(1-carbamoylpiperidin-4-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-35);N-(3-(1-methylpiperidin-4-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-36);N-(3-(1-isopropylpiperidin-4-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-37);N-(3-(1-cyclobutylpiperidin-4-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-38);N-(3-(1-cyclopentylpiperidin-4-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-39);N-(3-(1-cyclopropylpiperidin-4-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-40);N-(1-(p-tolyl)-3-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-41);N-(3-(piperidin-3-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-42);N-(3-(1-(methylsulfonyl)piperidin-3-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-43);N-(3-(1-(cyclopropylsulfonyl)piperidin-3-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-44);N-(3-((tetrahydro-2H-pyran-4-yl)methyl)-1-(p-tolyl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-45);N-(3-(tetrahydro-2H-pyran-4-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-46);N-(3-(1-isopropylpiperidin-4-yl)-1-(4-methoxyphenyl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-47);N-(1-(2,4-difluorophenyl)-3-(1-methylpiperidin-4-yl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-48);N-(3-(1-cyclobutylpiperidin-4-yl)-1-(2,4-difluorophenyl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-49);N-(1-(4-chloro-2-fluorophenyl)-3-(1-methylpiperidin-4-yl)-1H-pyrazol-5-yl)pyrazolo-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-50);N-(1-(4-chloro-2-fluorophenyl)-3-(1-cyclobutylpiperidin-4-yl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-51);N-(1-(4-cyclopropylphenyl)-3-(piperidin-4-yl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-52);N-(1-(4-cyclopropylphenyl)-3-(1-(methylsulfonyl)piperidin-4-yl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-53);N-(1-(4-cyclopropylphenyl)-3-(1-(cyclopropylsulfonyl)piperidin-4-yl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-54);N-(1-(4-cyclopropylphenyl)-3-(1-isopropylpiperidin-4-yl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-55);N-(1-(2-fluoro-4-methylphenyl)-3-(piperidin-4-yl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-56);N-(1-(2-fluoro-4-methylphenyl)-3-(1-(methylsulfonyl)piperidin-4-yl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-57);N-(1-(2-fluoro-4-methylphenyl)-3-(1-isopropylpiperidin-4-yl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-58);N-(3-(1-cyclobutylpiperidin-4-yl)-1-(2-fluoro-4-methylphenyl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-59);N-(1-(2-fluoro-4-methylphenyl)-3-(1-methylpiperidin-4-yl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-60);N-(1-(2-fluoro-4-methoxyphenyl)-3-(piperidin-4-yl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-61);N-(1-(2-fluoro-4-methoxyphenyl)-3-(1-isopropylpiperidin-4-yl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-62);N-(3-(1-(cyclopropylsulfonyl)piperidin-4-yl)-1-(2-fluoro-4-methoxyphenyl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-63);N-(1-(2-fluoro-4-methoxyphenyl)-3-(1-(methylsulfonyl)piperidin-4-yl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-64);N-(1-(2-chloro-4-methylphenyl)-3-(piperidin-4-yl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-65);N-(1-(2-chloro-4-methylphenyl)-3-(1-isopropylpiperidin-4-yl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-66);N-(1-(3,5-difluorophenyl)-3-(piperidin-4-yl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-67);N-(1-(4-fluoro-2-methylphenyl)-3-(piperidin-4-yl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-68);N-(1-(4-fluoro-2-methylphenyl)-3-(1-isopropylpiperidin-4-yl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-69);N-(1-(4-bromo-2-fluorophenyl)-3-(piperidin-4-yl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-70);N-(1-(4-bromo-2-fluorophenyl)-3-(1-(methylsulfonyl)piperidin-4-yl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-71);N-(1-(4-cyclopropyl-2-fluorophenyl)-3-(piperidin-4-yl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-72);N-(1-(4-cyclopropyl-2-fluorophenyl)-3-(1-(methylsulfonyl)piperidin-4-yl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-73);N-(1-(4-cyclopropyl-2-fluorophenyl)-3-(1-isopropylpiperidin-4-yl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-74);N-(3-(1-cyclobutylpiperidin-4-yl)-1-(4-cyclopropyl-2-fluorophenyl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-75);N-(1-(4-cyclopropyl-2-fluorophenyl)-3-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-76);N-(1-(4-cyclopropyl-2,6-difluorophenyl)-3-(piperidin-4-yl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-77);N-(3-(piperidin-4-yl)-1-(tetrahydro-2H-pyran-4-yl)-11′-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-78);N-(3-(morpholin-3-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-79);N-(3-(pyrrolidin-3-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-80);N-(3-(1-(methylsulfonyl)pyrrolidin-3-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-81);N-(3-(azetidin-3-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-82);N-(3-(1-(methylsulfonyl)azetidin-3-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-83);N-(3-(1-(cyclopropylsulfonyl)azetidin-3-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-84);N-(3-(1-(cyclopentylsulfonyl)azetidin-3-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-85);N-(3-(1-((2-methoxyethyl)sulfonyl)azetidin-3-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-86);N-(3-(azetidin-3-yl)-1-(4-cyclopropyl-2-fluorophenyl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-87);N-(1-(4-cyclopropyl-2-fluorophenyl)-3-(1-isopropylazetidin-3-yl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-88);N-(3-(1-cyclobutylazetidin-3-yl)-1-(4-cyclopropyl-2-fluorophenyl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-89);N-(1-(4-acetylphenyl)-3-(1-(methylsulfonyl)piperidin-4-yl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-90);N-(3-(4-methylpiperidin-4-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-91);N-(3-(4-methyl-1-(methylsulfonyl)piperidin-4-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-92); methyl4-(5-(pyrazolo[1,5-a]pyrimidine-3-carboxamido)-1-(p-tolyl)-1H-pyrazol-3-yl)cyclohexanecarboxylate(PTM-II-93);4-(5-(pyrazolo[1,5-]pyrimidine-3-carboxamido)-1-(p-tolyl)-1H-pyrazol-3-yl)cyclohexanecarboxylicacid (PTM-II-94);N-(3-(4-carbamoylcyclohexyl)-1-(p-tolyl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-95);N-(3-(4-(dimethylcarbamoyl)cyclohexyl)-1-(p-tolyl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-96);N-(1-(p-tolyl)-3-(4-(trifluoromethyl)cyclohexyl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-97);N-(3-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-98);N-(3-(4-sulfamoylphenyl)-1-(p-tolyl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-99);N-(1-(2-fluoro-4-methylphenyl)-3-(4-(N-methylsulfamoyl)phenyl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-100);N-(1-(4-cyclopropyl-2-fluorophenyl)-3-(4-(N-methylsulfamoyl)phenyl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-101);N-(3-(4-aminophenyl)-1-(p-tolyl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-102);N-(3-(4-(methylsulfonamido)phenyl)-1-(p-tolyl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-103);6-bromo-N-(1-(4-methoxyphenyl)-3-(piperidin-4-yl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-104);N3-(1-(4-methoxyphenyl)-3-(piperidin-4-yl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3,6-dicarboxamide(PTM-II-105);6-cyclopropyl-N-(1-(4-methoxyphenyl)-3-(piperidin-4-yl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-106);6-bromo-N-(3-(piperidin-4-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-107);6-bromo-N-(3-(1-isopropylpiperidin-4-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-108);6-bromo-N-(3-(1-(tetrahydro-2H-pyran-3-yl)piperidin-4-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-109);6-bromo-N-(3-(1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-110);6-bromo-N-(3-(1-methylpiperidin-4-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-111);6-bromo-N-(3-(1-(2-hydroxyacetyl)piperidin-4-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-112);6-bromo-N-(3-(1-(3-(dimethylamino)propanoyl)piperidin-4-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-113);6-bromo-N-(3-(1-(3-(diethylamino)propanoyl)piperidin-4-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-114);N-(3-(1-(2-amino-2-oxoethyl)piperidin-4-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)-6-bromopyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-115);6-bromo-N-(3-(1-(1-hydroxycyclobutanecarbonyl)piperidin-4-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-116);6-bromo-N-(3-(1-(4-methylmorpholine-2-carbonyl)piperidin-4-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-117); methyl4-(5-(6-bromopyrazolo[1,5-a]pyrimidine-3-carboxamido)-1-(p-tolyl)-1H-pyrazol-3-yl)piperidine-1-carboxylate(PTM-II-118);6-bromo-N-(3-(1-(methylsulfonyl)piperidin-4-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-119);N3-(3-(1-(methylsulfonyl)piperidin-4-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3,6-dicarboxamide(PTM-II-120);6-cyano-N-(3-(1-(methylsulfonyl)piperidin-4-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-121);6-methyl-N-(3-(1-(methylsulfonyl)piperidin-4-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-122);N-(3-(pyridin-3-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-123);N-(3-(6-methoxypyridin-3-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-124);N-(3-(pyridin-4-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-125);N-(1-(4-fluorophenyl)-3-(pyridin-4-yl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-126);N-(1-(4-methoxyphenyl)-3-(pyridin-4-yl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-127);N-(1-(3-fluoro-4-methylphenyl)-3-(pyridin-4-yl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-128);N-(3-(2-methoxypyridin-4-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-129);N-(3-cyclopropyl-1-(p-tolyl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-130);N-(3-(4-methoxyphenyl)-1-(p-tolyl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-131);N-(1-(3-fluorophenyl)-3-(4-methoxyphenyl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-132);N-(3-(3,4-dimethoxyphenyl)-1-(p-tolyl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-133);N-(3-(4-(methylsulfonyl)phenyl)-1-(p-tolyl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-134);N-(3-(4-fluorophenyl)-1-(p-tolyl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-135);N-(3-(5-fluoropyridin-3-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-136);N-(3-(pyrimidin-5-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-137);N-(3-(1,2,3,6-tetrahydropyridin-4-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-138);N-(3-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-139);N-(3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-140);N-(3-(4-(morpholinosulfonyl)phenyl)-1-(p-tolyl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-141);N-(3-(pyrrolidin-1-ylmethyl)-1-(p-tolyl)-1,4-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-142);N-(3-(4-(pyrrolidin-1-ylmethyl)phenyl)-1-(p-tolyl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-143);N-(3-(4-((4-methylpiperazin-1-yl)methylphenyl)-1-(p-tolyl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-144);N-(3-(4-(morpholinomethyl)phenyl)-1-(p-tolyl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-145);N-(1-(4-cyclopropylphenyl)-3-(piperidin-4-yl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-146);N-(1-(5-cyclopropylpyridin-2-yl)-3-(1-methylpiperidin-4-yl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-147);N-(3-(1-cyclobutylpiperidin-4-yl)-1-(5-cyclopropylpyridin-2-yl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-148);N-(1-(5-cyclopropylpyridin-2-yl)-3-(1-(methylsulfonyl)piperidin-4-yl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-149);N-(1-(5-cyclopropylpyridin-2-yl)-3-(1-(cyclopropylsulfonyl)piperidin-4-yl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-150);N-(1-(5-cyclopropylpyridin-2-yl)-3-(4-(N-methylsulfamoyl)phenyl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-151);N-(1-(5-methylpyridin-2-yl)-3-(piperidin-4-yl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-152);N-(1-(5-methylpyridin-2-yl)-3-(1-(methylsulfonyl)piperidin-4-yl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-153);N-(3-(1-(cyclopropylsulfonyl)piperidin-4-yl)-1-(5-methylpyridin-2-yl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-154);N-(1-(5-trideuteromethylpyridin-2-yl)-3-(1-(methylsulfonyl)piperidin-4-yl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-155);N-(1-(5-methoxypyridin-2-yl)-3-(1-(methylsulfonyl)piperidin-4-yl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-156);N-(1-(5-(aminomethyl)pyridin-2-yl)-3-(1-(methylsulfonyl)piperidin-4-yl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-157);N-(1-(5-(1-amino-2-methylpropan-2-yl)pyridin-2-yl)-3-(1-(methylsulfonyl)piperidin-4-yl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-158);N-(1-(5-(2-aminopropan-2-yl)pyridin-2-yl)-3-(1-(methylsulfonyl)piperidin-4-yl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-159);N-(1-(5-carbamoylpyridin-2-yl)-3-(piperidin-4-yl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(160);N-(1-(5-(1-(methylamino)ethyl)pyridin-2-yl)-3-(1-(methylsulfonyl)piperidin-4-yl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-161);N-(1-(5-(hydroxymethyl)pyridin-2-yl)-3-(1-(methylsulfonyl)piperidin-4-yl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-162);(R)—N-(1-(5-(1-aminoethyl)pyridin-2-yl)-3-(1-(methylsulfonyl)piperidin-4-yl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-163);(S)—N-(1-(5-(1-aminoethyl)pyridin-2-yl)-3-(1-(methylsulfonyl)piperidin-4-yl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-164);N-(1-(5-formylpyridine-2-yl)-3-(1-(methylsulfonyl)piperidin-4-yl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-165);N-(1-(5-methylpyridin-2-yl)-3-(morpholin-3-yl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-166);N-(1-(6-methylpyridin-3-yl)-3-(piperidin-4-yl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-167);N-(1-(6-methylpyridin-3-yl)-3-(1-(methylsulfonyl)piperidin-4-yl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-168);N-(1-(5-methylpyrimidin-2-yl)-3-(piperidin-4-yl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-169);N-(1-(5-methylpyrimidin-2-yl)-3-(1-(methylsulfonyl)piperidin-4-yl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-170);N-(3-(1-(cyclopropylsulfonyl)piperidin-4-yl)-1-(5-methylpyrimidin-2-yl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-171);N-(1-(5-methylpyrazin-2-yl)-3-(1-(methylsulfonyl)piperidin-4-yl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-172);N-(3-(1-(methylsulfonyl)piperidin-4-yl)-1-(pyridin-2-yl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-173);N-(1-(5,6-dimethylpyridin-2-yl)-3-(1-(methylsulfonyl)piperidin-4-yl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-174);N-(1-(1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-(1-(methylsulfonyl)piperidin-4-yl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(175);N-(1-(5-(aminomethyl)pyridin-2-yl)-3-(1-methylcyclopropyl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-176);N-(1-(5-methylpyridin-2-yl)-3-(4-(morpholinosulfonyl)phenyl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-177);N-(3-(4-((4-methylpiperazin-1-yl)sulfonyl)phenyl)-1-(5-methylpyridin-2-yl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-178);N-(1-(5-methylpyridin-2-yl)-3-(4-(methylsulfonyl)phenyl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-179);N-(3-cyclopropyl-1-(5-methylpyridin-2-yl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-180);N-(3-(1-methylcyclopropyl)-1-(5-methylpyridin-2-yl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-181);N-(3-methoxy-1-(5-methylpyridin-2-yl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-182);methyl((4-(5-(pyrazolo[1,5-a]pyrimidine-3-carboxamido)-1-(p-tolyl)-1H-pyrazol-3-yl)cyclohexyl)methyl)carbamate(PTM-II-183);N-(3-(4-(aminomethyl)cyclohexyl)-1-(p-tolyl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-184);N-(3-(4-aminocyclohexyl)-1-(5-methylpyridin-2-yl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-185);N-(1-(2-aminoethyl)-3-(1-(methylsulfonyl)piperidin-4-yl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-186);N-(1-(1H-imidazol-2-yl)-3-(1-isopropylpiperidin-4-yl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-187);N-(1-(1-(methylsulfonyl)-1H-imidazol-2-yl)-3-(1-(methylsulfonyl)piperidin-4-yl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-188);N-(3-(piperidin-4-yl)-1-(thiazol-2-yl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-189);6-bromo-N-(1-(5-methylpyridin-2-yl)-3-(1-(methylsulfonyl)piperidin-4-yl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-190);6-cyano-N-(1-(5-methylpyridin-2-yl)-3-(1-(methylsulfonyl)piperidin-4-yl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-191);N3-(3-(1-(methylsulfonyl)piperidin-4-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3,6-dicarboxamide(PTM-II-192);6-ethynyl-N-(1-(5-methylpyridin-2-yl)-3-(1-(methylsulfonyl)piperidin-4-yl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-193);6-bromo-N-(1-(5-methylpyridin-2-yl)-3-(4-(N-methylsulfamoyl)phenyl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-194);6-cyclopropyl-N-(1-(5-methylpyridin-2-yl)-3-(4-(N-methylsulfamoyl)phenyl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-195);6-chloro-N-(1-(5-methylpyridin-2-yl)-3-(4-(N-methylsulfamoyl)phenyl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-196);N-(3-(4-methylpiperazin-1-yl)-1-(5-methylpyridin-2-yl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-197);N-(3-(4-methylpiperazin-1-yl)-1-(5-trideuteromethylpyridin-2-yl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-198);N-(1-(5-methylpyridin-2-yl)-3-(4-(methylsulfonyl)piperazin-1-yl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-199);N-(1-(5-trideuteromethylpyridin-2-yl)-3-(4-(methylsulfonyl)piperazin-1-yl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-200);N-(1-(5-cyclopropylpyridin-2-yl)-3-(4-methylpiperazin-1-yl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-201);N-(1-(5-methylpyridin-2-yl)-3-morpholino-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-202);N-[3-(1′-acetyl-1,4′-bipiperidin-4-yl)-1-(4-methylphenyl)-1H-pyrazol-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-203);N-[3-(1-cyclohexylpiperidin-4-yl)-1-(4-methylphenyl)-1H-pyrazol-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-204);N-[3-(1-cyclobutylpiperidin-4-yl)-1-(4-methylphenyl)-1H-pyrazol-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-205);N-[3-(1′-methyl-1,4′-bipiperidin-4-yl)-1-(4-methylphenyl)-1H-pyrazol-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-206);N-{1-(4-methylphenyl)-3-[1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl]-1H-pyrazol-5-yl}pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-207); ethyl4-{1-(4-methylphenyl)-5-[(pyrazolo[1,5-a]pyrimidin-3-ylcarbonyl)amino]-1H-pyrazol-3-yl}-1,4′-bipiperidine-1′-carboxylate(PTM-II-208);N-(3-(1-(3-methylbutan-2-yl)piperidin-4-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-209);N-(3-(1-(sec-butyl)piperidin-4-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-210);N-(3-(1-(1-methoxypropan-2-yl)piperidin-4-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-211):N-(3-(1-(1-(3-fluoropyridin-2-yl)ethyl)piperidin-4-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-212);N-(3-(1-(1-oxo-1-(piperidin-1-yl)propan-2-yl)piperidin-4-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-213);N-(3-(1-(1-oxo-1-(pyrrolidin-1-yl)propan-2-yl)piperidin-4-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-214);N-(3-(1-(1-(6-fluoropyridin-2-yl)ethyl)piperidin-4-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-215);N-[3-(1t-cyclopropyl-1,4′-bipiperidin-4-yl)-1-(4-methylphenyl)-1H-pyrazol-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-216);N-[1-(4-methylphenyl)-3-{1-[1-(1,3-thiazol-2-yl)ethyl]piperidin-4-yl}-1H-pyrazol-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-217);N-[3-(1-benzylpiperidin-4-yl)-1-(4-methylphenyl)-1H-pyrazol-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-218);N-{1-(4-methylphenyl)-3-[1-(2-methylpropyl)piperidin-4-yl]-1H-pyrazol-5-yl}pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-219);N-[1-(4-methylphenyl)-3-(1-propylpiperidin-4-yl)-1H-pyrazol-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-220);N-{3-[1-(cyclopropylmethyl)piperidin-4-yl]-1-(4-methylphenyl)-1H-pyrazol-5-yl}pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-221);N-{1-(4-methylphenyl)-3-[1-(1,3-thiazol-2-ylmethyl)piperidin-4-yl]-1H-pyrazol-5-yl}pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-222);N-{1-(4-methylphenyl)-3-[1-(thiophen-3-ylmethyl)piperidin-4-yl]-1H-pyrazol-5-yl}pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-223);N-(3-(1-(pyridin-4-ylmethyl)piperidin-4-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-224);N-{1-(4-methylphenyl)-3-[1-(pyridin-3-ylmethyl)piperidin-4-yl]-1H-pyrazol-5-yl}pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-225);N-{1-(4-methylphenyl)-3-[1-(pyridin-2-ylmethyl)piperidin-4-yl]-1H-pyrazol-5-yl}pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-226);N-[3-{1-[(6-methoxypyridin-3-yl)methyl]piperidin-4-yl}-1-(4-methylphenyl)-1H-pyrazol-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-227);N-{1-(4-methylphenyl)-3-[1-(tetrahydrofuran-3-ylmethyl)piperidin-4-yl]-1H-pyrazol-5-yl}pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-228);N-{1-(4-methylphenyl)-3-[1-(1,3-thiazol-5-ylmethyl)piperidin-4-yl]-1H-pyrazol-5-yl}pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-229);N-{1-(4-methylphenyl)-3-[1-(1H-pyrazol-5-ylmethyl)piperidin-4-yl]-1H-pyrazol-5-yl}pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-230);N-{1-(4-methylphenyl)-3-[1-(1,3-thiazol-4-ylmethyl)piperidin-4-yl]-1H-pyrazol-5-yl}pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-231);N-{1-(4-methylphenyl)-3-[1-(1,3-oxazol-2-ylmethyl)piperidin-4-yl]-1H-pyrazol-5-yl}pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-232);N-{1-(4-methylphenyl)-3-[1-(1H-pyrazol-4-ylmethyl)piperidin-4-yl]-1H-pyrazol-5-yl}pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-233); N-[3-(1-azetidin-3-ylpiperidin-4-yl)-1-(4-methylphenyl)-1H-pyrazol-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-234);N-[3-(1-{1-[(1-methylethyl)carbamoyl]azetidin-3-yl}piperidin-4-yl)-1-(4-methylphenyl)-1H-pyrazol-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-235);N-[3-{1-[1-(tert-butylcarbamoyl)azetidin-3-yl]piperidin-4-yl]-1-(4-methylphenyl)-1H-pyrazol-5-yl}pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-236);N-[3-{1-[1-(ethylcarbamoyl)azetidin-3-yl]piperidin-4-yl}-1-(4-methylphenyl)-1H-pyrazol-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-237); methyl3-(4-{1′-(4-methylphenyl)-5-[(pyrazolo[1,5-a]pyrimidin-3-ylcarbonyl)amino]-1H-pyrazol-3-yl}piperidin-1-yl)azetidine-1-carboxylate(PTM-II-238); ethyl3-(4-{1-(4-methylphenyl)-5-[(pyrazolo[1,5-a]pyrimidin-3-ylcarbonyl)amino]-1H-pyrazol-3-yl}piperidin-1-yl)azetidine-1-carboxylate(PTM-II-239); 1-methylethyl3-(4-{1-(4-methylphenyl)-5-[(pyrazolo[1,5-a]pyrimidin-3-ylcarbonyl)amino]-1H-pyrazol-3-yl}piperidin-1-yl)azetidine-1-carboxylate(PTM-II-240); 2-fluoroethyl3-(4-{1-(4-methylphenyl)-5-[(pyrazolo[1,5-a]pyrimidin-3-ylcarbonyl)amino]-1H-pyrazol-3-yl}piperidin-1-yl)azetidine-1-carboxylate(PTM-II-241); 2-methoxyethyl3-(4-{1-(4-methylphenyl)-5-[(pyrazolo[1,5-a]pyrimidin-3-ylcarbonyl)amino]-1H-pyrazol-3-yl}piperidin-1-yl)azetidine-1-carboxylate(PTM-II-242);N-[3-{1-[1-(ethylsulfonyl)azetidin-3-yl]piperidin-4-yl}-1-(4-methylphenyl)-1H-pyrazol-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-243);N-[1-(4-methylphenyl)-3-{1-[1-(methylsulfonyl)azetidin-3-yl]piperidin-4-yl}-1H-pyrazol-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-244);N-[3-{1-[1-(cyclopropylsulfonyl)azetidin-3-yl]piperidin-4-yl]-1-(4-methylphenyl)-1H-pyrazol-5-yl}pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-245); N-[3-(1-{1-[(1-methylethyl)sulfonyl]azetidin-3-yl}piperidin-4-yl)-1-(4-methylphenyl)-1H-pyrazol-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-246);N-[3-(1-{1-[(fluoromethyl)sulfonyl]azetidin-3-yl]piperidin-4-yl)-1-(4-methylphenyl)-1H-pyrazol-5-yl}pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-247);N-{3-[1-(1-acetylazetidin-3-yl)piperidin-4-yl]-1-(4-methylphenyl)-1H-pyrazol-5-yl}pyrazolopyrimidine-3-carboxamide (PTM-II-248);N-{1-(4-methylphenyl)-3-[1-(1-propanoylazetidin-3-yl)piperidin-4-yl]-1H-pyrazol-5-yl}pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-249);N-[1-(4-methylphenyl)-3-{1-[4-(trifluoromethyl)cyclohexyl]piperidin-4-yl}-1H-pyrazol-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-250);N-[3-(1-{4-[methyl(methylsulfonyl)amino]cyclohexyl}piperidin-4-yl)-1-(4-methylphenyl)-1H-pyrazol-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-251);N-[1-(4-methylphenyl)-3-(1-{4-[(methylsulfonyl)amino]cyclohexyl}piperidin-4-yl)-1H-pyrazol-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-252);N-{3-[1-(4-cyanocyclohexyl)piperidin-4-yl]-1-(4-methylphenyl)-1H-pyrazol-5-yl}pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-253);N-[3-(1-bicyclo[3.1.0]hex-2-ylpiperidin-4-yl)-1-(4-methylphenyl)-1H-pyrazol-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-254);N-{1-(4-methylphenyl)-3-[1-(2-oxo-1-azaspiro[4.5]dec-8-yl)piperidin-4-yl]-1H-pyrazol-5-yl}pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-255);N-{3-[1-(3-tert-butylcyclobutyl)piperidin-4-yl]-1-(4-methylphenyl)-1H-pyrazol-5-yl}pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-256);N-[1-(4-methylphenyl)-3-(1-spiro[3.4]oct-2-ylpiperidin-4-yl)-1H-pyrazol-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-257);N-{3-[1-(3-cyanocyclobutyl)piperidin-4-yl]-1-(4-methylphenyl)-1H-pyrazol-5-yl}pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-258);N-{3-[1-(4,4-difluorocyclohexyl)piperidin-4-yl]-1-(4-methylphenyl)-1H-pyrazol-5-yl}pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-259);N-{1-(4-methylphenyl)-3-[1-(3,3,3-trifluoro-1-methylpropyl)piperidin-4-yl]-1H-pyrazol-5-yl}pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-260); tert-butyl3-(4-{1-(4-methylphenyl)-5-[(pyrazolo[1,5-a]pyrimidin-3-ylcarbonyl)amino]-1H-pyrazol-3-yl}piperidin-1-yl)azetidine-1-carboxylate(PTM-II-261);N-[3-(1-{4-[methyl(methylsulfonyl)amino]cyclohexyl}piperidin-4-yl)-1-(5-methylpyridin-2-yl)-1H-pyrazol-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-262);N-[1-(5-methylpyridin-2-yl)-3-(1-{4-[(methylsulfonyl)amino]cyclohexyl]piperidin-4-yl)-1H-pyrazol-5-yl}pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-263);N-{1-(5-methylpyridin-2-yl)-3-[1-(tetrahydro-2H-pyran-3-yl)piperidin-4-yl]-1H-pyrazol-5-yl}pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-264);N-{3-[1-(4-cyanocyclohexyl)piperidin-4-yl]-1-(5-methylpyridin-2-yl)-1H-pyrazol-5-yl}pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-265); N-[3-{1-[1-(4-fluorophenyl)pyrrolidin-3-yl]piperidin-4-yl]-1-(5-methylpyridin-2-yl)-1H-pyrazol-5-yl}pyrazolo-[1,5-a]pyrimidine-3-carboxamide(PTM-II-266);N-[3-(1′-cyclopropyl-1,4′-bipiperidin-4-yl)-1-(5-methylpyridin-2-yl)-1H-pyrazol-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-267);N-{1-(5-methylpyridin-2-yl)-3-[1-(5,6,7,8-tetrahydroisoquinolin-7-yl)piperidin-4-yl]-1H-pyrazol-5-yl}pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-268);N-[3-{1-[3-(dimethylamino)cyclobutyl]piperidin-4-yl}-1-(5-methylpyridin-2-yl)-1H-pyrazol-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-269);N-{3-[1-(1-methylethyl)piperidin-4-yl]-1-(5-methylpyridin-2-yl)-1H-pyrazol-5-yl}pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-270);N-[1-(5-methylpyridin-2-yl)-3-{1-[4-(trifluoromethyl)cyclohexyl]piperidin-4-yl}-1H-pyrazol-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-271);N-{3-[1-(3-methylcyclopentyl)piperidin-4-yl]-1-(5-methylpyridin-2-yl)-1H-pyrazol-5-yl}pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-272);N-[3-{1-[(3R)-3-methylcyclopentyl]piperidin-4-yl}-1-(5-methylpyridin-2-yl)-1H-pyrazol-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-273);N-[3-(1-cyclobutylpiperidin-4-yl)-1-(5-methylpyridin-2-yl)-1H-pyrazol-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-274);N-[3-(1′-methyl-1,4′-bipiperidin-4-yl)-1-(5-methylpyridin-2-yl)-1H-pyrazol-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-275); ethyl4-{1-(5-methylpyridin-2-yl)-5-[(pyrazolo[1,5-a]pyrimidin-3-ylcarbonyl)amino]-1H-pyrazol-3-yl}-1,4′-bipiperidine-1′-carboxylate(PTM-II-276);N-{3-[1-(3-methylcyclohexyl)piperidin-4-yl]-1-(5-methylpyridin-2-yl)-1H-pyrazol-5-yl}pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-277);N-{3-[1-(2-methylpropyl)piperidin-4-yl]-1-(5-methylpyridin-2-yl)-1H-pyrazol-5-yl}pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-278);N-[3-(1′-ethyl-1,4′-bipiperidin-4-yl)-1-(5-methylpyridin-2-yl)-1H-pyrazol-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-279);N-[1-(5-methylpyridin-2-yl)-3-(1-propylpiperidin-4-yl)-1H-pyrazol-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-280);N-{3-[1-(cyclopropylmethyl)piperidin-4-yl]-1-(5-methylpyridin-2-yl)-1H-pyrazol-5-yl}pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-281);N-{3-[1-(2,3-dihydro-1H-inden-2-yl)piperidin-4-yl]-1-(5-methylpyridin-2-yl)-1H-pyrazol-5-yl}pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-282);N-{1-(4-methylphenyl)-3-[1-(tetrahydrofuran-3-ylmethyl)piperidin-3-yl]-1H-pyrazol-5-yl}pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-283);N-{1-(4-methylphenyl)-3-[1-(1,3-thiazol-5-ylmethyl)piperidin-3-yl]-1H-pyrazol-5-yl}pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-284);N-[1-(4-methylphenyl)-3-{1-[(3-oxo-2,3-dihydro-1H-isoindol-5-yl)methyl]piperidin-3-yl}-1H-pyrazol-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-285);N-[3-(1-{[2-(dimethylamino)-1,3-thiazol-5-yl]methyl}piperidin-3-yl)-1-(4-methylphenyl)-1H-pyrazol-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-286);N-{1-(4-methylphenyl)-3-[1-(1H-pyrazol-5-ylmethyl)piperidin-3-yl]-1H-pyrazol-5-yl}pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-287);N-{1-(4-methylphenyl)-3-[1-(1,3-thiazol-4-ylmethyl)piperidin-3-yl]-1H-pyrazol-5-yl}pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-288);N-{1-(4-methylphenyl)-3-[1-(1,3-oxazol-2-ylmethyl)piperidin-3-yl]-1H-pyrazol-5-yl}pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-289);N-[3-{1-[(2-fluoropyridin-3-yl)methyl]piperidin-3-yl}-1-(4-methylphenyl)-1H-pyrazol-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-290);N-[3-{1-[(2-methoxypyrimidin-5-yl)methyl]piperidin-3-yl}-1-(4-methylphenyl)-1H-pyrazol-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-291);N-[3-{1-[(5-fluoropyridin-2-yl)methyl]piperidin-3-yl}-1-(4-methylphenyl)-1H-pyrazol-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-292);N-[3-{1-[4-(3-cyanooxetan-3-3/1)benzyl]piperidin-3-yl}-1-(4-methylphenyl)-1H-pyrazol-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-293);N-{1-(4-methylphenyl)-3-[1-(1H-pyrazol-4-ylmethyl)piperidin-3-yl]-1H-pyrazol-5-yl}pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-294);N-[1-(4-methylphenyl)-3-{1-[(1-oxo-2,3-dihydro-1H-isoindol-4-yl)methyl]piperidin-3-yl}-1H-pyrazol-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-295);N-[1-(4-methylphenyl)-3-{1-[4-(methylsulfonyl)benzyl]piperidin-3-yl}-1H-pyrazol-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-296);N-{3-[1-(cyclopropylmethyl)piperidin-3-yl]-1-(4-methylphenyl)-1H-pyrazol-5-yl}pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-297);N-{1-(4-methylphenyl)-3-[1-(1,3-thiazol-2-ylmethyl)piperidin-3-yl]-1H-pyrazol-5-yl}pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-298);N-{1-(4-methylphenyl)-3-[1-(pyridin-4-ylmethyl)piperidin-3-yl]-1H-pyrazol-5-yl}pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-299);N-{1-(4-methylphenyl)-3-[1-(pyridin-3-ylmethyl)piperidin-3-yl]-1H-pyrazol-5-yl}pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-300);N-{1-(4-methylphenyl)-3-[1-(pyridin-2-ylmethyl)piperidin-3-yl]-1H-pyrazol-5-yl}pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-301);N-[3-{1-[(6-methoxypyridin-3-yl)methyl]piperidin-3-yl}-1-(4-methylphenyl)-1H-pyrazol-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-302);N-[3-{1-[(1-ethyl-1H-pyrazol-5-yl)methyl]piperidin-3-yl}-1-(4-methylphenyl)-1H-pyrazol-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-303);N-{1-(4-methylphenyl)-3-[1-(pyrazin-2-ylmethyl)azetidin-3-yl]-1H-pyrazol-5-yl}pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-304);N-{1-(4-methylphenyl)-3-[1-(1H-pyrazol-4-ylmethyl)azetidin-3-yl]-1H-pyrazol-5-yl}pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-305);N-{1-(4-methylphenyl)-3-[1-(1H-pyrazol-5-ylmethyl)azetidin-3-yl]-1H-pyrazol-5-yl}pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-306);N-{1-(4-methylphenyl)-3-[1-(1,3-thiazol-2-ylmethyl)azetidin-3-yl]-1H-pyrazol-5-yl}pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-307);N-{1-(4-methylphenyl)-3-[1-(pyridin-2-ylmethyl)azetidin-3-yl]-1H-pyrazol-5-yl}pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-308);N-{1-(4-methylphenyl)-3-[1-(pyridin-4-ylmethyl)azetidin-3-yl]-1H-pyrazol-5-yl}pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-309);N-{1-(4-methylphenyl)-3-[1-(pyrimidin-5-ylmethyl)azetidin-3-yl]-1H-pyrazol-5-yl}pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-310);N-[3-{1-[(5-methylisoxazol-3-yl)methyl]azetidin-3-yl]-1-(4-methylphenyl)-1H-pyrazol-5-yl}pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-311);N-{1-(4-methylphenyl)-3-[1-(1,3-thiazol-5-ylmethyl)azetidin-3-yl]-1H-pyrazol-5-yl}pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-312); N-[3-{1-[(2-methoxypyridin-3-yl)methyl]azetidin-3-yl}-1-(4-methylphenyl)-1H-pyrazol-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-313);N-{1-(4-methylphenyl)-3-[1-(pyridin-3-ylmethyl)azetidin-3-yl]-1H-pyrazol-5-yl}pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-314);N-[3-{1-[(6-methoxypyridin-2-yl)methyl]azetidin-3-yl}-1-(4-methylphenyl)-1H-pyrazol-5-yl]pyrazolopyrimidine-3-carboxamide (PTM-II-315);N-{1-(4-methylphenyl)-3-[1-(1,3-oxazol-2-ylmethyl)azetidin-3-yl]-1H-pyrazol-5-yl}pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-316);N-[3-{1-[(2-methoxypyrimidin-5-yl)methyl]azetidin-3-yl}-1-(4-methylphenyl)-1H-pyrazol-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-317);N-{1-(4-methylphenyl)-3-[1-(1,3-oxazol-4-ylmethyl)azetidin-3-yl]-1H-pyrazol-5-yl}pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-318);N-[3-(4-cyclohexylpiperazin-1-yl)-1-(5-methylpyridin-2-yl)-1H-pyrazol-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-319);N-[3-(4-cyclobutylpiperazin-1-yl)-1-(5-methylpyridin-2-yl)-1H-pyrazol-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-320);N-{1-(5-methylpyridin-2-yl)-3-[4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl]-1H-pyrazol-5-yl}pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-321);N-[3-(4-cycloheptylpiperazin-1-yl)-1-(5-methylpyridin-2-yl)-1H-pyrazol-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-322);N-[3-(4-cyclopentylpiperazin-1-yl)-1-(5-methylpyridin-2-yl)-1H-pyrazol-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-323);N-{3-[4-(2-methylpropyl)piperazin-1-yl]-1-(5-methylpyridin-2-yl)-1H-pyrazol-5-yl}pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-324);N-(3-(1-cyclopentylpiperidin-4-yl)-1-(p-tolyl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-325);N-[1′-methyl-1-(4-methylphenyl)-1H,1′H-3,4′-bipyrazol-5-]pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-326);N-{1-(4-methylphenyl)-3-[5-(4-methylpiperazin-1-yl)pyridin-3-yl]-1H-pyrazol-5-yl}pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-327);N-{1-(4-methylphenyl)-3-[2-(piperidin-1-ylmethyl)pyridin-4-yl]-1H-pyrazol-5-yl}pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-328);N-{3-[2-(hydroxymethyl)pyridin-4-yl]-1-(4-methylphenyl)-1H-pyrazol-5-yl}pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-329);N-{3-[6-(hydroxymethyl)pyridin-3-yl]-1-(4-methylphenyl)-1H-pyrazol-5-yl}pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-330);N-[2′-methyl-1-(4-methylphenyl)-1H,2′H-3,3′-bipyrazol-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-331);N-{3-[5-(hydroxymethyl)pyridin-3-yl]-1-(4-methylphenyl)-1H-pyrazol-5-yl}pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-332); N-{1-(4-methylphenyl)-1′-[2-(methylsulfonyl)ethyl]-1H,1′H-3,4′-bipyrazol-5-yl}pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-333);N-[3-(3-methylisoxazol-4-yl)-1-(4-methylphenyl)-1H-pyrazol-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-334);N-[1-(4-methylphenyl)-3-(2-morpholin-4-yl-1,3-thiazol-4-yl)-1H-pyrazol-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-335);N-{3-[4-(cyclopropylsulfonyl)phenyl]-1-(4-methylphenyl)-1H-pyrazol-5-yl}pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-336);N-[3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(4-methylphenyl)-1H-pyrazol-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-337);N-{1-(4-methylphenyl)-3-[4-(methylsulfonyl)-2-(trifluoromethyl)phenyl]-1H-pyrazol-5-yl}pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-338);N-{3-[2-(benzyloxy)-6-fluorophenyl]-1-(4-methylphenyl)-1H-pyrazol-5-yl}pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-339);N-{3-[4-(diethylsulfamoyl)-2-methylphenyl]-1-(4-methylphenyl)-1H-pyrazol-5-yl}pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-340); N-[3-{4-[(1-methylethyl)sulfonyl]phenyl}-1-(4-methylphenyl)-1H-pyrazol-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-341); N-[1-(4-methylphenyl)-3-{4-[(4-methylpiperazin-1-yl)sulfonyl]phenyl}-1H-pyrazol-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-342);N-{3-[4-(diethylsulfamoyl)phenyl]-1-(4-methylphenyl)-1H-pyrazol-5-yl}pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-343);N-{3-[4-(azetidin-1-ylsulfonyl)phenyl]-1-(4-methylphenyl)-1H-pyrazol-5-yl}pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-344);N-{3-[4-(dimethylsulfamoyl)-2-methylphenyl]-1-(4-methylphenyl)-1H-pyrazol-5-yl}pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-345);N-[1-(4-methylphenyl)-3-{3-[(methylsulfonyl)amino]phenyl}-1H-pyrazol-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-346);N-{1-(4-methylphenyl)-3-[4-(methylsulfamoyl)phenyl]-1H-pyrazol-5-yl}pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-347);N-{3-[4-(methylcarbamoyl)phenyl]-1-(4-methylphenyl)-1H-pyrazol-5-yl}pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-348);N-{3-[4-(dimethylcarbamoyl)phenyl]-1-(4-methylphenyl)-1H-pyrazol-5-yl}pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-349);N-{3-[3-(methylcarbamoyl)phenyl]-1-(4-methylphenyl)-1H-pyrazol-5-yl}pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-350);N-{1-(4-methylphenyl)-3-[6-(methylsulfonyl)pyridin-3-yl]-1H-pyrazol-5-yl}pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-351);N-{3-[4-(ethylsulfonyl)phenyl]-1-(4-methylphenyl)-1H-pyrazol-5-yl}pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-352);N-{3-[4-(dimethylsulfamoyl)phenyl]-1-(4-methylphenyl)-1H-pyrazol-5-yl}pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-353);N-[3-(1-methyl-6-oxo-1,2,3,6-tetrahydropyridin-4-yl)-1-(4-methylphenyl)-1H-pyrazol-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-354);N-[3-(2-aminopyridin-4-yl)-1-(4-methylphenyl)-1H-pyrazol-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-355); N-[3-{1-[(1,2-benzisoxazol-3-ylmethyl)sulfonyl]piperidin-4-yl}-1-(4-methylphenyl)-1H-pyrazol-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-356);N-{1-(4-methylphenyl)-3-[1-(naphthalen-1-ylsulfonyl)piperidin-4-yl]-1H-pyrazol-5-yl}pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-357);N-[1-(4-methylphenyl)-3-{1-[(pyridin-4-ylmethyl)sulfonyl]piperidin-4-yl}-1H-pyrazol-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-358); N-[3-{1-[(3,4-dimethoxyphenyl)sulfonyl]piperidin-4-yl}-1-(4-methylphenyl)-1H-pyrazol-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-359);N-[3-{1-[(3,5-difluorophenyl)sulfonyl]piperidin-4-yl}-1-(4-methylphenyl)-1H-pyrazol-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-360);N-{1-(4-methylphenyl)-3-[1-(propylsulfonyl)piperidin-4-yl]-1H-pyrazol-5-yl}pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-361);N-[3-{1-[(2-cyanophenyl)sulfonyl]piperidin-4-yl}-1-(4-methylphenyl)-1H-pyrazol-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-362);N-[1-(4-methylphenyl)-3-{1-[(3,3,3-trifluoropropyl)sulfonyl]piperidin-4-yl}-1H-pyrazol-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-363);N-[3-{1-[(2,4-dimethyl-1,3-thiazol-5-yl)sulfonyl]piperidin-4-yl}-1-(4-methylphenyl)-1H-pyrazol-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-364);N-3-{1-[(3,4-difluorophenyl)sulfonyl]piperidin-4-yl}-1-(4-methylphenyl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-365); N-[3-{1[(4-fluorophenyl)sulfonyl]piperidin-4-yl}-1-(4-methylphenyl)-1H-pyrazol-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-366);N-[3-{1-[(4-methoxyphenyl)sulfonyl]piperidin-4-yl}-1-(4-methylphenyl)-1H-pyrazol-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-367);N-[3-{1-[(1-methylethyl)sulfonyl]piperidin-4-yl}-1-(4-methylphenyl)-1H-pyrazol-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-368);N-{3-[1-(butylsulfonyl)piperidin-4-yl]-1-(4-methylphenyl)-1H-pyrazol-5-yl}pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-369);N-[3-{1-[(2,4-difluorophenyl)sulfonyl]piperidin-4-yl}-1-(4-methylphenyl)-1H-pyrazol-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-370);N-[1-(4-methylphenyl)-3-(1-{[3-(trifluoromethyl)phenyl]sulfonyl}piperidin-4-yl)-1H-pyrazol-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-371);N-[3-{1-[(2,4-dimethoxyphenyl)sulfonyl]piperidin-4-yl}-1-(4-methylphenyl)-1H-pyrazol-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-372);N-{3-[1-(cyclohexylsulfonyl)piperidin-4-yl]-1-(4-methylphenyl)-1H-pyrazol-5-yl}pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-373);N-[3-{1-[(3-cyanophenyl)sulfonyl]piperidin-4-yl}-1-(4-methylphenyl)-1H-pyrazol-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-374);N-[1-(4-methylphenyl)-3-{1-[(1-methyl-1H-pyrazol-4-yl)sulfonyl]piperidin-4-yl}-1H-pyrazol-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-375);N-[3-{1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]piperidin-4-yl}-1-(4-methylphenyl)-1H-pyrazol-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-376);N-{1-(4-methylphenyl)-3-[1-(naphthalen-2-ylsulfonyl)piperidin-4-yl]-1H-pyrazol-5-yl}pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-377);N-[3-{1-[(2-fluorophenyl)sulfonyl]piperidin-4-yl}-1-(4-methylphenyl)-1H-pyrazol-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-378);N-[3-{1-[(3-fluorophenyl)sulfonyl]piperidin-4-yl}-1-(4-methylphenyl)-1H-pyrazol-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-379);N-[3-{1-[(4-cyanophenyl)sulfonyl]piperidin-4-yl}-1-(4-methylphenyl)-1H-pyrazol-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-380);N-[1-(4-methylphenyl)-3-(1-{[4-(trifluoromethyl)phenyl]sulfonyl}piperidin-4-yl)-1H-pyrazol-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-381);N-[3-{1-[(4-chloropyridin-3-yl)sulfonyl]piperidin-4-yl}-1-(4-methylphenyl)-1H-pyrazol-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-382);N-[1-(4-methylphenyl)-3-{1-[(6-morpholin-4-ylpyridin-3-yl)sulfonyl]piperidin-4-yl}-1H-pyrazol-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-383);N-{3-[1-(1,3-benzothiazol-6-ylsulfonyl)piperidin-4-yl]-1-(4-methylphenyl)-1H-pyrazol-5-yl}pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-384);N-[3-{1-[(3-methoxyphenyl)sulfonyl]piperidin-4-yl}-1-(4-methylphenyl)-1H-pyrazol-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-385);N-[3-{1-[(1,2-dimethyl-1H-imidazol-4-yl)sulfonyl]piperidin-4-yl}-1-(4-methylphenyl)-1H-pyrazol-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-386);N-{3-[1-(benzylsulfonyl)piperidin-4-yl]-1-(4-methylphenyl)-1H-pyrazol-5-yl}pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-387);N-[3-{1-[(2-chloropyridin-3-yl)sulfonyl]piperidin-4-yl}-1-(4-methylphenyl)-1H-pyrazol-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-388);N-[3-{1-[(6-methoxypyridin-3-yl)sulfonyl]piperidin-4-yl}-1-(4-methylphenyl)-1H-pyrazol-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-389); N-[3-{1-[(2,6-dichlorophenyl)sulfonyl]piperidin-4-yl}-1-(4-methylphenyl)-1H-pyrazol-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-390); N-[3-{1[(2,4-dichlorophenyl)sulfonyl]piperidin-4-yl}-1-(4-methylphenyl)-1H-pyrazol-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-391); N-[1-(4-methylphenyl)-3-{1-[(pyridin-3-ylmethyl)sulfonyl]piperidin-4-yl}-1H-pyrazol-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-392); N-[3-{1-[(5-chlorothiophen-2-yl)sulfonyl]piperidin-4-yl}-1-(4-methylphenyl)-1H-pyrazol-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-393);N-[1-(4-methylphenyl)-3-(1-{[6-(trifluoromethyl)pyridin-2-yl]sulfonyl}piperidin-4-yl)-1H-pyrazol-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-394); N-[1-(4-methylphenyl)-3-{1-[(2-phenylethyl)sulfonyl]piperidin-4-yl}-1H-pyrazol-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-395);N-{1-(4-methylphenyl)-3-[1-(quinolin-8-ylsulfonyl)piperidin-4-yl]-1H-pyrazol-5-yl}pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-396); N-[1-(4-methylphenyl)-3-{1-[(pyridin-2-ylmethyl)sulfonyl]piperidin-4-yl}-1H-pyrazol-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-397);N-(1-(4-cyclopropyl-2-fluorophenyl)-3-(1-methylpiperidin-4-yl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-398); andN-(3-(1-methylpiperidin-4-yl)-1-(5-methylpyridin-2-yl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(PTM-II-399).

In any aspect or embodiment described herein, the PTM is represented byFormula PTM-III (which correspond to Formula I from U.S. PatentApplication Publication No. 2015/0133451 A1, which is incorporatedherein in its entirety for all purposes):

wherein

-   -   R¹ of PTM-III is an optionally substituted aromatic heterocyclic        group or an optionally substituted C₆₋₁₄ aryl group;    -   R² of PTM-III is a hydrogen atom or a substituent;    -   R³ and R⁴ of PTM-III are independently a hydrogen atom or a        substituent, or R³ and R⁴ in combination optionally form an        optionally substituted ring;    -   R⁵ and R⁶ of PTM-III are independently a hydrogen atom or a        substituent, or R⁵ and R⁶ in combination optionally form an        optionally substituted ring;    -   X of PTM-III is CR⁷R⁸, NR⁹, O or S;    -   R⁷ and R⁸ of PTM-III are independently a hydrogen atom or a        substituent, or R⁷ and R⁸ in combination optionally form an        optionally substituted ring;    -   R⁹ of PTM-III is a hydrogen atom or a substituent; and    -   the PTM-III is covalently joined to a ULM, a chemical linker        group (L), a CLM, an ILM, a VLM, MLM, a ULM′, a CLM′, a ILM′, a        VLM′, a MLM′, or combination thereof.

In any aspect or embodiment described herein, the PTM-I is covalentlyjoined to a ULM, a chemical linker group (L), a CLM, an ILM, a VLM, MLM,a ULM′, a CLM′, a ILM′, a VLM′, a MLM′, or combination thereof via an Rgroup (e.g., R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, or R⁹).

In any aspect or embodiment described herein, the “substituent” ofPTM-III may include a halogen atom, a cyano group, a nitro group, anoptionally substituted hydrocarbon group, an optionally substitutedheterocyclic group, an acyl group, an optionally substituted aminogroup, an optionally substituted carbamoyl group, an optionallysubstituted thiocarbamoyl group, an optionally substituted sulfamoylgroup, an optionally substituted hydroxy group, an optionallysubstituted sulfanyl (SH) group and an optionally substituted silylgroup. Furthermore, the substituent may be independently selected fromthe group consisting of: a halogen atom, a nitro group, a cyano group,an oxo group, a hydroxy group, an optionally halogenated C₁₋₆ alkoxygroup, a C₆₋₁₄ aryloxy group (e.g., phenoxy, naphthoxy), a C₇₋₁₆aralkyloxy group (e.g., benzyloxy), a 5- to 14-membered aromaticheterocyclyloxy group (e.g., pyridyloxy), a 3- to 14-memberednon-aromatic heterocyclyloxy group (e.g., morpholinyloxy,piperidinyloxy), a C₁₋₆ alkyl-carbonyloxy group (e.g., acetoxy,propanoyloxy), a C₆₋₁₄ aryl-carbonyloxy group (e.g., benzoyloxy,naphthoyloxy, 2-naphthoyloxy), a C₁₋₆ alkoxy-carbonyloxy group (e.g.,methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy,butoxycarbonyloxy), a mono- or di-C₁₋₆ alkyl-carbamoyloxy group (e.g.,methylcarbamoyloxy, ethylcarbamoyloxy, dimethylcarbamoyloxy,diethylcarbamoyloxy), a C₆₋₁₄ aryl-carbamoyloxy group (e.g.,phenylcarbamoyloxy, naphthylcarbamoyloxy), a 5- to 14-membered aromaticheterocyclylcarbonyloxy group (e.g., nicotinoyloxy), a 3- to 14-memberednon-aromatic heterocyclylcarbonyloxy group (e.g.,morpholinylcarbonyloxy, piperidinylcarbonyloxy), an optionallyhalogenated C₁₋₆ alkylsulfonyloxy group (e.g., methylsulfonyloxy,trifluoromethylsulfonyloxy), a C₆₋₁₄ arylsulfonyloxy group optionallysubstituted by a C₁₋₆ alkyl group (e.g., phenylsulfonyloxy,toluenesulfonyloxy), an optionally halogenated C₁₋₆ alkylthio group, a5- to 14-membered aromatic heterocyclic group, a 3- to 14-memberednon-aromatic heterocyclic group, a formyl group, a carboxy group, anoptionally halogenated C₁₋₆ alkyl-carbonyl group, a C₆₋₁₄ aryl-carbonylgroup, a 5- to 14-membered aromatic heterocyclylcarbonyl group, a 3- to14-membered non-aromatic heterocyclylcarbonyl group, a C₁₋₆alkoxy-carbonyl group, a C₆₋₁₄ aryloxy-carbonyl group (e.g.,phenyloxycarbonyl, 1-naphthyloxycarbonyl, 2-naphthyloxycarbonyl), aC₇₋₁₆ aralkyloxy-carbonyl group (e.g., benzyloxycarbonyl,phenethyloxycarbonyl), a carbamoyl group, a thiocarbamoyl group, a mono-or di-C₁₋₆ alkyl-carbamoyl group, a C₆₋₁₄ aryl-carbamoyl group (e.g.,phenylcarbamoyl), a 5- to 14-membered aromatic heterocyclylcarbamoylgroup (e.g., pyridylcarbamoyl, thienylcarbamoyl), a 3- to 14-memberednon-aromatic heterocyclylcarbamoyl group (e.g., morpholinylcarbamoyl,piperidinylcarbamoyl), an optionally halogenated C₁₋₆ alkylsulfonylgroup, a C₆₋₁₄ arylsulfonyl group, a 5- to 14-membered aromaticheterocyclylsulfonyl group (e.g., pyridylsulfonyl, thienylsulfonyl), anoptionally halogenated C₁-6 alkylsulfinyl group, a C₆₋₁₄ arylsulfinylgroup (e.g., phenylsulfinyl, 1-naphthylsulfinyl, 2-naphthylsulfinyl), a5- to 14-membered aromatic heterocyclylsulfinyl group (e.g.,pyridylsulfinyl, thienylsulfinyl), an amino group, a mono- or di-C₁₋₆alkylamino group (e.g., methylamino, ethylamino, propylamino,isopropylamino, butylamino, dimethylamino, diethylamino, dipropylamino,dibutylamino, N-ethyl-N-methylamino), a mono- or di-C₆₋₁₄ arylaminogroup (e.g., phenylamino), a 5- to 14-membered aromaticheterocyclylamino group (e.g., pyridylamino), a C₇₋₁₆ aralkylamino group(e.g., benzylamino), a formylamino group, a C₁₋₆ alkyl-carbonylaminogroup (e.g., acetylamino, propanoylamino, butanoylamino), a (C₁₋₆ alkyl)(C₁₋₆ alkyl-carbonyl)amino group (e.g., N-acetyl-N-methylamino), a C₆₋₁₄aryl-carbonylamino group (e.g., phenylcarbonylamino,naphthylcarbonylamino), a C₁₋₆ alkoxy-carbonylamino group (e.g.,methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino,butoxycarbonylamino, tert-butoxycarbonylamino), a C₇₋₁₆aralkyloxy-carbonylamino group (e.g., benzyloxycarbonylamino), a C₁₋₆alkylsulfonylamino group (e.g., methylsulfonylamino,ethylsulfonylamino), a C₆₋₁₄ arylsulfonylamino group optionallysubstituted by a C₁₋₆ alkyl group (e.g., phenylsulfonylamino,toluenesulfonylamino), an optionally halogenated C₁₋₆ alkyl group, aC₂₋₆ alkenyl group, a C₂₋₆ alkynyl group, a C₃₋₁₀ cycloalkyl group, aC₃₋₁₀ cycloalkenyl group and a C₆₋₁₄ aryl group.

The term “optionally substituted hydrocarbon group” of PTM-III includesa hydrocarbon group optionally having substituent(s) independentlyselected from the group consisting of: a halogen atom, a nitro group, acyano group, an oxo group, a hydroxy group, an optionally halogenatedC₁₋₆ alkoxy group, a C₆₋₁₄ aryloxy group (e.g., phenoxy, naphthoxy), aC₇-16 aralkyloxy group (e.g., benzyloxy), a 5- to 14-membered aromaticheterocyclyloxy group (e.g., pyridyloxy), a 3- to 14-memberednon-aromatic heterocyclyloxy group (e.g., morpholinyloxy,piperidinyloxy), a C₁₋₆ alkyl-carbonyloxy group (e.g., acetoxy,propanoyloxy), a C₆₋₁₄ aryl-carbonyloxy group (e.g., benzoyloxy,naphthoyloxy, 2-naphthoyloxy), a C₁₋₆ alkoxy-carbonyloxy group (e.g.,methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy,butoxycarbonyloxy), a mono- or di-C₁₋₆ alkyl-carbamoyloxy group (e.g.,methylcarbamoyloxy, ethylcarbamoyloxy, dimethylcarbamoyloxy,diethylcarbamoyloxy), a C₆₋₁₄ aryl-carbamoyloxy group (e.g.,phenylcarbamoyloxy, naphthylcarbamoyloxy), a 5- to 14-membered aromaticheterocyclylcarbonyloxy group (e.g., nicotinoyloxy), a 3- to 14-memberednon-aromatic heterocyclylcarbonyloxy group (e.g.,morpholinylcarbonyloxy, piperidinylcarbonyloxy), an optionallyhalogenated C₁₋₆ alkylsulfonyloxy group (e.g., methylsulfonyloxy,trifluoromethylsulfonyloxy), a C₆₋₁₄ arylsulfonyloxy group optionallysubstituted by a C₁₋₆ alkyl group (e.g., phenylsulfonyloxy,toluenesulfonyloxy), an optionally halogenated C₁₋₆ alkylthio group, a5- to 14-membered aromatic heterocyclic group, a 3- to 14-memberednon-aromatic heterocyclic group, a formyl group, a carboxy group, anoptionally halogenated C₁₋₆ alkyl-carbonyl group, a C₆₋₁₄ aryl-carbonylgroup, a 5- to 14-membered aromatic heterocyclylcarbonyl group, a 3- to14-membered non-aromatic heterocyclylcarbonyl group, a C₁₋₆alkoxy-carbonyl group, a C₆₋₁₄ aryloxy-carbonyl group (e.g.,phenyloxycarbonyl, 1-naphthyloxycarbonyl, 2-naphthyloxycarbonyl), aC₇₋₁₆ aralkyloxy-carbonyl group (e.g., benzyloxycarbonyl,phenethyloxycarbonyl), a carbamoyl group, a thiocarbamoyl group, a mono-or di-C₁₋₆ alkyl-carbamoyl group, a C₆₋₁₄ aryl-carbamoyl group (e.g.,phenylcarbamoyl), a 5- to 14-membered aromatic heterocyclylcarbamoylgroup (e.g., pyridylcarbamoyl, thienylcarbamoyl), a 3- to 14-memberednon-aromatic heterocyclylcarbamoyl group (e.g., morpholinylcarbamoyl,piperidinylcarbamoyl), an optionally halogenated C₁₋₆ alkylsulfonylgroup, a C₆₋₁₄ arylsulfonyl group, a 5- to 14-membered aromaticheterocyclylsulfonyl group (e.g., pyridylsulfonyl, thienylsulfonyl), anoptionally halogenated C₁-6 alkylsulfinyl group, a C₆₋₁₄ arylsulfinylgroup (e.g., phenylsulfinyl, 1-naphthylsulfinyl, 2-naphthylsulfinyl), a5- to 14-membered aromatic heterocyclylsulfinyl group (e.g.,pyridylsulfinyl, thienylsulfinyl), an amino group, a mono- or di-C₁₋₆alkylamino group (e.g., methylamino, ethylamino, propylamino,isopropylamino, butylamino, dimethylamino, diethylamino, dipropylamino,dibutylamino, N-ethyl-N-methylamino), a mono- or di-C₆₋₁₄ arylaminogroup (e.g., phenylamino), a 5- to 14-membered aromaticheterocyclylamino group (e.g., pyridylamino), a C₇₋₁₆ aralkylamino group(e.g., benzylamino), a formylamino group, a C₁₋₆ alkyl-carbonylaminogroup (e.g., acetylamino, propanoylamino, butanoylamino), a (C₁₋₆ alkyl)(C₁₋₆ alkyl-carbonyl)amino group (e.g., N-acetyl-N-methylamino), a C₆₋₁₄aryl-carbonylamino group (e.g., phenylcarbonylamino,naphthylcarbonylamino), a C₁₋₆ alkoxy-carbonylamino group (e.g.,methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino,butoxycarbonylamino, tert-butoxycarbonylamino), a C₇₋₁₆aralkyloxy-carbonylamino group (e.g., benzyloxycarbonylamino), a C₁₋₆alkylsulfonylamino group (e.g., methylsulfonylamino,ethylsulfonylamino), a C₆₋₁₄ arylsulfonylamino group optionallysubstituted by a C₁₋₆ alkyl group (e.g., phenylsulfonylamino,toluenesulfonylamino), an optionally halogenated C₁₋₆ alkyl group, aC₂₋₆ alkenyl group, a C₂₋₆ alkynyl group, a C₃₋₁₀ cycloalkyl group, aC₃₋₁₀ cycloalkenyl group and a C₆₋₁₄ aryl group.

In any aspect or embodiments described herein, the PTM of PTM-IIIcomprises at least one of:

-   -   R¹ of PTM-III is an aromatic, heterocyclic group or a C₆₋₁₄ aryl        group, each of which is optionally substituted by 1 to 3        substituents selected from a halogen atom, an optionally        substituted C₁₋₆ alkyl group, an optionally substituted C₆₋₁₄        aryl group, an optionally substituted heterocyclic group, a        C₃₋₁₀ cycloalkylsulfonyl group, a C₁₋₆ alkyl-carbonyl group, an        aromatic heterocyclylsulfonyl group and a halogenated sulfanyl        group;    -   R² of PTM-III is an optionally substituted C₁₋₆ alkyl group, an        optionally substituted C₃₋₁₀ cycloalkyl group or an optionally        substituted non-aromatic heterocyclic group;    -   R³ and R⁴ of PTM-III are independently a hydrogen atom or an        optionally substituted C₁₋₆ alkyl group;    -   R⁵ and R⁶ of PTM-III are independently (1) a hydrogen atom, (2)        a hydroxy group, (3) an optionally substituted C₁₋₆ alkyl        group, (4) an optionally substituted C₁₋₆ alkoxy group, (5) an        amino group optionally mono- or di-substituted by substituent(s)        selected from (i) an optionally substituted C₁₋₆ alkyl        group, (ii) an optionally substituted C₁₋₆ alkyl-carbonyl group,        and (iii) an optionally substituted C₁₋₆ alkylsulfonyl        group, (6) an optionally substituted non-aromatic heterocyclic        group, (7) a carboxy group, or (8) a carbamoyl group optionally        mono- or di-substituted by C₁₋₆ alkyl group(s), or R⁵ and R⁶ in        combination optionally form an optionally substituted        non-aromatic heterocycle or an optionally substituted C₃₋₁₀        cycloalkane;    -   X of PTM-III is CR⁷R⁸, NR⁹, O or S;    -   R⁷ and R⁸ of PTM-III are independently a hydrogen atom, a cyano        group, an optionally substituted C₁₋₆ alkyl group or a hydroxy        group, or R⁷ and R⁸ in combination optionally form an optionally        substituted C₃₋₁₀ cycloalkane or an optionally substituted        non-aromatic heterocycle; and    -   R⁹ of PTM-III is a hydrogen atom, an optionally substituted C₁₋₆        alkyl group, an optionally substituted C₂₋₆ alkenyl group or an        optionally substituted C₇₋₁₆ aralkyl group.

In any aspect or embodiment described herein, the PTM of PTM-IIIcomprises at least one of: X is CR⁷R⁸ or NR⁹; and R³ and R⁴ are bothhydrogen atoms.

In any aspect or embodiment described herein, the PTM of PTM-III isselected from the group consisting of:N-(3-(3-(2-Hydroxyethyl)-2-oxoimidazolidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2-((2,2,2-trifluoroethyl)amino)pyridin-4-yl)-1,3-oxazole-4-carboxamide(PTM-III-1);N-(1-Methyl-3-(2-oxoimidazolidin-1-yl)-1H-pyrazol-4-yl)-2-(2-((2,2,2-trifluoroethyl)amino)pyridin-4-yl)-1,3-oxazole-4-carboxamide(PTM-III-2); andN-(1-Methyl-3-((3S)-3-methyl-2-oxopyrrolidin-1-yl)-1H-pyrazol-4-yl)-2-(2-((2,2,2-trifluoroethyl)amino)pyridin-4-yl)-1,3-oxazole-4-carboxamide(PTM-III-3).

In any aspect or embodiment described herein, the PTM is represented byFormula PTM-IV (which correspond to Formula I from U.S. PatentApplication Publication No. 2015/0191464 A1, which is incorporatedherein in its entirety for all purposes):

wherein:

-   -   HET of PTM-IV is a heteroaryl selected from pyrazolyl, indolyl,        pyrrolo[2,3-b]pyridinyl, pyrrolo[2,3-d]pyrimidinyl,        pyrazolo[3,4-b]pyridinyl, pyrazolo[3,4-d]pyrimidinyl,        2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, imidazo[4,5-b]pyridinyl,        and purinyl, wherein said heteroaryl is substituted with R_(a)        and R_(b);    -   R_(a) of PTM-IV is H, F, Cl, Br, —CN, —OH, C₁₋₄ alkyl, C₁₋₄        fluoroalkyl, C₁₋₄ hydroxyalkyl, C₁₋₄ alkoxy, —NH₂, —NH(C₁₋₄        alkyl), —N(C₁₋₄ alkyl)₂, —NH(C₁₋₄ hydroxyalkyl), NH(C₁₋₄        fluoroalkyl), —NH(C₁₋₆ hydroxy-fluoroalkyl), —C(O)NH₂,        —CH₂NHC(O)(C₁₋₆ alkyl), —CH₂NHC(O)(C₁₋₆ hydroxyalkyl),        —CH₂NHC(O)NH(C₁₋₆ alkyl), CH₂NHC(O)NHCH₂(phenyl),        —CH₂NHC(O)N(C₁₋₄ alkyl)₂, —CH₂NHC(O)O(C₁₋₄ alkyl),        —CH₂NHC(O)(C₃₋₆ cycloalkyl), —CH₂NHC(O)(tetrahydrofuranyl),        CH₂NHC(O)CH₂(C₃₋₆ cycloalkyl), —CH₂NHC(O)CH₂(tetrahydropyranyl),        CH2NHC(O)CH₂(phenyl), —NHC(O)(C₁₋₄ alkyl), pyrrolidinyl,        hydroxypyrrolidinyl, or pyridazinyl;    -   R_(b) of PTM-IV is H or —NH₂;    -   R₁ of PTM-IV is: (i) C₁₋₆ alkyl, C₁₋₆ fluoroalkyl, C₁₋₆        hydroxyalkyl, C₁₋₈ hydroxy-fluoroalkyl, —(C₁₋₆ alkylenyl)O(C₁₋₄        alkyl), —(C₁₋₆ alkylenyl)O(C₁₋₄ fluoroalkyl), —(C₁₋₆        fluoroalkylenyl)O(C₁₋₄ alkyl), —(C₁₋₆ fluoroalkylenyl)O(C₁₋₄        deuteroalkyl), —(C₁₋₆ fluoroalkylenyl)O(C₁₋₄ fluoroalkyl),        —(C₁₋₄ fluoroalkylenyl)C(C₃₋₆ cycloalkyl)₂(OH), (C₁₋₄        alkylenyl)NHC(O)(C₁₋₄ alkylenyl)OC(O)(C₁₋₃ alkyl), —(C₁₋₆        alkylenyl)NHS(O)₂(C₁₋₄ alkyl), —(C₁₋₆ alkylenyl)_(P)(O)(C₁₋₄        alkoxy)₂, —(C₁₋₆ fluoroalkylenyl)NH(C₁₋₄ alkyl), (C₁₋₆        alkylenyl)C(O)NH(C₁₋₄ alkyl), —(C₁₋₆ fluoroalkylenyl)C(O)NH(C₁₋₄        alkyl), —(C₁₋₆ fluoroalkylenyl)C(O)NH(C₁₋₄ hydroxyalkyl), or        —(C₁₋₆ fluoroalkylenyl)OP(O)(OH)₂; (ii) —(C₁₋₃ alkylenyl)R_(x),        —(C₁₋₃ fluoroalkylenyl)R_(x), —(C₁₋₃ alkylenyl)C(O)R_(x), —(C₁₋₃        alkylenyl)C(O)NHR_(x), —(C₁₋₃ fluoroalkylenyl)C(O)R_(x), or        —CH₂CF=(tetrahydropyranyl), wherein R_(x) is a cyclic group        selected from C₃₋₆ cycloalkyl, tetrazolyl,        1,1-dioxidotetrahydrothiophenyl, 1,1-dioxidothiomorpholinyl,        oxadiazolyl, piperidinyl, piperazinyl, pyrrolidinyl, oxetanyl,        tetrahydrofuranyl, tetrahydropyranyl, pyridinyl, imidazolyl,        morpholinyl, phenyl, and triazinyl, wherein each cyclic group is        substituted with zero to 3 substituents independently selected        from F, —OH, —CH₃, —C(CH₂)₂OH, —OCH₃, —C(O)CH₂CN, —S(O)₂CH₃,        —S(O)₂NH₂, —NHC(O)CH₃, —N(S(O)₂CH₃)₂, —CH₂CH₂(acetamidophenyl),        —CH₂CH₂(methoxyphenyl), —CH₂CH₂ (sulfamoylphenyl), oxetanyl,        benzyl, and morpholinyl; (iii) C3-6 cycloalkyl or C4-6        cycloalkenyl, each substituted with zero to 3 substituents        independently selected from F, —OH, —CN, C1-3 alkyl, C1-3        alkoxy, —S(C1-3 alkyl), —NO2, —S(O)2(C1-3 alkyl), C1-4        hydroxyalkyl, —C(C1-3 alkyl)(OH)(C3-6 cycloalkyl),        —CH2C(O)NH(C1-3 alkyl), —NHC(O)(C1-3 alkyl), —NHC(O)(C1-4        hydroxyalkyl), —C(O)NH(C1-3 alkyl), C(O)NH(C1-3 deuteroalkyl),        —C(O)NH(C3-6 cycloalkyl), —NHC(O)O(C1-3 alkyl), NHS(O)2(C1-3        alkyl), pyridinyl, imidazolyl, pyrazolyl, methylimidazolyl,        methylpyrazolyl, and thiazolyl; (iv) tetrahydropyranyl,        piperidinyl, pyrazolyl, phenyl, pyridinyl, or pyrimidinyl, each        substituted with zero to 1 substituent selected from —OH, C1-3        alkyl, C1-3 fluoroalkyl, C1-4 hydroxyalkyl, C1-3 alkoxy,        —C(O)(C1-4 alkyl), S(O)2(C1-4 alkyl), —S(O)2NH(C1-4 alkyl),        —NH(C1-3 alkyl), —N(C1-3 alkyl)2, O(C1-3 alkylenyl)N(C1-3        alkyl)2, —CH2(morpholinyl), azetidinyl, oxetanyl,        tetrahydropyranyl, morpholinyl, piperazinyl, piperidinyl,        methylpiperazinyl, methoxypiperidinyl, pyridinyl, pyrimidinyl,        methylsulfonyl azetidinyl, and C(O)(methylsulfonyl azetidinyl);        or (v) pyrrolo[2,3-c]pyridinyl, bicyclo[2.2.1]heptan-1-ol,        tetrahydrobenzo[d]thiazol-2-amine, or        1,3-diazaspiro[4.5]decane-2,4-dione;    -   R₂ is: (i) C₁₋₇ alkyl or C₂₋₆ alkenyl, each substituted with        zero to three substituents independently selected from F, —OH,        and —CN; —(C₁₋₄ alkylenyl)O(C₁₋₄ alkyl), —(C₁₋₄ alkylenyl)O(C₁₋₄        fluoroalkyl), —(C₁₋₆ alkylenyl)NH2, —(C₁₋₆ alkylenyl)S(O)₂(C₁₋₃        alkyl), —(C₁₋₆ fluoroalkylenyl)NH(C₁₋₃ alkyl), or —(C₁₋₆        alkylenyl)NHC(O)(C₁₋₄ fluoroalkyl); (ii) —(C₁₋₄ alkylenyl)R_(y)        wherein R_(y) is C₃₋₆ cycloalkyl, azetidinyl, oxetanyl,        oxazolyl, pyridinyl, tetrahydropyranyl, or morpholinyl, each        substituted with zero to 2 substituents independently selected        from F, —OH, and C₁₋₃ alkyl; (iii) C₃₋₆ cycloalkyl, azetidinyl,        oxetanyl, furanyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl,        or tetrahydropyranyl, each substituted with zero to 3        substituents independently selected from F, —OH, C₁₋₃ alkyl,        C₁₋₃ hydroxyalkyl, —C(O)(C₁₋₃ alkyl), —C(O)(C₁₋₃ fluoroalkyl),        —C(O)(C₁₋₃ cyanoalkyl), —C(O)O(C₁₋₃ alkyl), —C(O)NH₂,        —C(O)NH(C₁₋₃ alkyl), —C(O)(difluorophenyl), NH₂, —NH(C₁₋₃        alkyl), —NH(C₁₋₃ fluoroalkyl), —NH(oxetanyl), —NHC(O)(C₁₋₃        alkyl), —NHC(O)(C₁₋₃ fluoroalkyl), —NHC(O)(C₃₋₆ cycloalkyl),        —NHC(O)(fluorophenyl), —S(O)₂(C₁₋₃ alkyl), imidazolyl, phenyl,        pyrimidinyl, fluoropyrimidinyl, chloropyrimidinyl, and        methoxypyrimidinyl; (iv) adamantanyl, hydroxyadamantanyl,        benzo[d]imidazolyl, benzo[d]oxazolyl, benzo[d]triazolyl,        benzothiazolyl, bicyclo[1.1.1]pentanyl, or        hydroxybicyclo[2.2.1]heptanyl; or (v) phenyl, pyrazolyl,        thiazolyl, thiadiazolyl, or indazolyl, each substituted with 0        to 2 substituents independently selected from F, Cl, —OH, —CN,        C₁₋₄ alkyl, C₁₋₄ hydroxyalkyl, C₁₋₄ fluoroalkyl, C₁₋₄        cyanoalkyl, C₁₋₃ alkoxy, C₃₋₆ cycloalkyl, —(C₁₋₃        alkylenyl)O(C₁₋₃ alkyl), —(C₁₋₃ alkylenyl)O(C₁₋₃ fluoroalkyl),        —C(O)NH₂, C(O)NH(C₁₋₃ alkyl), —NHC(O)(C₁₋₃ alkyl),        —NHC(O)S(O)₂(C₁₋₃ alkyl), —S(O)₂NH₂, S(O)₂(C₁₋₃ alkyl),        pyrazolyl, methyl pyrazolyl, imidazolyl, triazolyl, methyl        tetrazolyl, ethyl tetrazolyl, phenyl, pyrimidinyl,        fluoropyrimidinyl, and tetrahydropyranyl; and    -   the PTM-IV is covalently joined to a ULM, a chemical linker        group (L), a CLM, an ILM, a VLM, MLM, a ULM′, a CLM′, a ILM′, a        VLM′, a MLM′, or combination thereof.

In any aspect or embodiment described herein, the PTM-IV is covalentlyjoined to a ULM, a chemical linker group (L), a CLM, an ILM, a VLM, MLM,a ULM′, a CLM′, a ILM′, a VLM′, a MLM′, or combination thereof via an Rgroup (e.g., R₁, R₂, R_(a) or R_(b)).

In any aspect or embodiment described herein, the HET group of PTM-IV isa heteroaryl group having at least one nitrogen heteroatom, wherein onenitrogen heteroatom of the HET group forms a bond to a carbon atomadjacent to the nitrogen heteroatom in the pyridine ring. For example,the HET may be a heteroaryl selected from

wherein:

-   -   R_(a) of PTM-IV is H, F, Cl, Br, —CN, —OH, —CH₃, —CHF₂, —OCH₃,        —NH₂, —N(CH₃)₂, —NHCH₂CH₂OH, —NHCH₂C(CH₃)₂OH,        —NHCH₂CHFC(CH₃)₂OH, —C(O)NH₂, —CH₂NHC(O)CH₂CH₂CH₃,        —CH₂NHC(O)CH(CH₃)₂, —CH₂NHC(O)CH₂CH(CH₃)₂, CH₂NHC(O)CH₂C(CH₃)₃,        —CH₂NHC(O)CH₂CH₂CH(CH₃)₂, —CH₂NHC(O)CH₂C(CH₃)₂OH,        —CH₂NHC(O)NHCH₂CH₂CH₃, —CH₂NHC(O)NHCH₂CH₂CH₂CH₃,        —CH₂NHC(O)NHCH₂(phenyl), CH₂NHC(O)N(CH₂CH₃)₂, —CH₂NHC(O)OCH₂CH₃,        —CH₂NHC(O)OCH₂CH(CH₃)₂, —CH₂NHC(O)(cyclopropyl),        —CH₂NHC(O)(tetrahydrofuranyl), CH₂NHC(O)CH₂(cyclopentyl),        —CH₂NHC(O)CH₂(cyclohexyl), CH₂NHC(O)CH₂(tetrahydropyranyl),        —CH₂NHC(O)CH₂(phenyl), —NHC(O)CH₃, hydroxypyrrolidinyl, or        pyridazinyl; and    -   R_(b) of PTM-IV is H or —NH₂.

In any aspect or embodiment described herein, at least one of:

-   -   R₁ of PTM-IV is: (i) —CH₃, —CH₂CH₃, —CH₂CH₂CH₃, —CH(CH₃)₂,        —CH₂CH₂CH₂CH₃, —CH₂CH(CH₃)₂, —C(CH₃)₃, —CH₂CH₂CH(CH₃)₂,        —CH₂CHFCH₃, —CH₂CH₂CF₂CH₃, —CH₂CHFCH(CH₃)₂, —CH₂CH₂C(CH₃)₂F,        —CH₂CHFC(CH₃)₂F, CH₂CH₂CH(OH)CH₃, —CH₂CH₂C(CH₃)₂OH,        —CH₂CHFCH(CH₃)OH, CH₂CHFC(CH₃)₂OH, —CH₂CF₂C(CH₃)₂OH,        —CH₂CHFC(CH₂CH₃)₂OH, CH₂CHFC(cyclopropyl)₂(OH),        —CH₂CHFCH(OH)CH(CH₃)₂, —CH₂CH₂OCH₂CH₃, (CH₂)₃OCH(CH₃)₂,        —(CH₂)₃₀C(CH₃)₃, —CH₂CHFCH₂OCH₃, CH₂CHFC(CH₃)₂OCH₃,        —CH₂CHFC(CH₃)₂₀CD₃, —CH₂CHFC(CH₃)₂OCHF₂, CH₂CHFC(CH₃)₂OCH₂CH₃,        —CH₂CH₂C(O)OCH₃, —CH₂CH₂NHC(O)C(CH₃)₂₀C(O)CH₃,        —CH₂CH₂NHS(O)₂CH₃, —CH₂CH₂CH(CH₃)NHS(O)₂CH₃,        —CH₂CH₂C(CH₃)₂NHS(O)₂CH₃, CH₂CH₂P(O)(OCH₂CH₃)₂,        —CH₂CHFCH(CH₃)NHCH(CH₃)₂, —CH₂CHFC(O)NHCH₃, —CH₂CH₂C(O)NHCH₂CH₃,        —CH₂CHFC(O)NHCH(CH₃)₂, —CH₂CHFC(O)NHCH(CH₃)CH₂OH, or        —CH₂CHFC(CH₃)₂OP(O)(OH)₂; (ii) —(C₁₋₃ alkylenyl)R_(x), —(C₁₋₂        fluoroalkylenyl)R_(x), —(C₁₋₂ alkylenyl)C(O)R_(x),        —CH₂C(O)NHR_(x), —CH₂CHFC(O)R_(x), or        —CH₂CF=(tetrahydropyranyl), wherein R_(x) is a cyclic group        selected from cyclopropyl, cyclopentyl, cyclohexyl, tetrazolyl,        1,1-dioxidotetrahydrothiophenyl, 1,1-dioxidothiomorpholinyl,        oxadiazolyl, piperidinyl, piperazinyl, pyrrolidinyl, oxetanyl,        tetrahydrofuranyl, tetrahydropyranyl, pyridinyl, imidazolyl,        morpholinyl, phenyl, and triazinyl, wherein each cyclic group is        substituted with zero to 3 substituents independently selected        from F, —OH, —CH₃, —C(CH₂)₂OH, —OCH₃, —C(O)CH₂CN, —S(O)₂CH₃,        —S(O)₂NH₂, —NHC(O)CH₃, —N(S(O)₂CH₃)₂, CH₂CH₂(acetamidophenyl),        —CH₂CH₂(methoxyphenyl), —CH₂CH₂(sulfamoylphenyl), oxetanyl,        benzyl, and morpholinyl; (iii) cyclopropyl, cyclopentyl,        cyclopentenyl, or cyclohexyl, each substituted with zero to 2        substituents independently selected from F, OH, —CN, —CH₃,        —OCH₃, —SCH₃, —NO₂, —S(O)₂CH₃, —C(CH₃)₂OH,        —C(CH₃)(OH)(cyclopropyl), —CH₂C(O)NHCH₃, —NHC(O)CH(OH)CH₃,        —C(O)NHCD₃, —C(O)NHCH₃, —C(O)NHCH₂CH₃, —C(O)NH(cyclopropyl),        —NHC(O)CH₃, NHC(O)OCH₃, —NHS(O)₂CH₃, pyridinyl,        methylimidazolyl, methylpyrazolyl, and thiazolyl; (iv)        tetrahydropyranyl, piperidinyl, pyrazolyl, phenyl, pyridinyl, or        pyrimidinyl, each substituted with zero to 1 substituent        selected from —OH, —OCH₃, —CH₂CHF₂, —C(CH₃)₂OH, —CH₂C(CH₃)₂OH,        —C(O)CH(CH₃)₂, —S(O)₂CH₃, —S(O)₂CH₂CH₃, S(O)₂CH(CH₃)₂,        —S(O)₂NHCH₃, —S(O)₂NHCH(CH₃)₂, —N(CH₃)₂, —OCH₂CH₂N(CH₃)₂,        —CH₂(morpholinyl), oxetanyl, tetrahydropyranyl, morpholinyl,        piperazinyl, methylpiperazinyl, methoxypiperidinyl, pyrimidinyl,        methylsulfonyl azetidinyl, and —C(O)(methylsulfonyl azetidinyl);        or (v) pyrrolo[2,3-c]pyridinyl, bicyclo[2.2.1]heptan-1-ol,        tetrahydrobenzo[d]thiazol-2-amine, or        1,3-diazaspiro[4.5]decane-2,4-dione; and    -   R₂ of PTM-IV is: (i) —CH₂CH₃, —CH₂CH₂CH₃, —CH(CH₃)₂, —C(CH₃)₃,        —CH₂C(CH₃)₃, —CH(CH₃)CH₂CH₃, —CH₂CH₂CH(CH₃)₂,        —CH(CH₃)CH₂CH(CH₃)₂, CH(CH₃)CH₂OH, —CH₂CH₂CH(CH₃)OH,        —CH(CH₃)CH₂CH₂OH, —CH₂C(CH₃)₂OH, —C(CH₃)₂CH₂OH,        —CH(CH₃)CH(OH)CH₂CH(CH₃)₂, —CH₂CH(OH)CH(CH₃)₂, CH(CH₂OH)CH₂CH₃,        —CH(CH₂OH)CH(CH₃)₂, —CH═CHC(CH₃)₂OH, —CH₂CH₂CN, —CH₂CHF₂,        —CH₂CF₃, —CH₂CHFCH₃, —CH(CH₃)CF₃, —CH₂CH₂CF₃, CH(CH₃)CH₂F,        —CH₂CH₂CH₂F, —CH₂CHFCH₂CH₃, —CH₂CH₂CHFCH₃, CH(CH₃)CHFCH₃,        —CH(CH₃)CH₂CH₂F, —CH₂CH₂C(CH₃)₂F, —CH₂CHFC(CH₃)₂OH,        —CH₂CF₂C(CH₃)₂OH, —CH₂C(CH₃)FCH₂OH, —CH(CH₂F)CH₂OH, CH₂CH₂OCHF₂,        —CH₂C(CH₃)OCHF₂, —CH₂C(CH₃)₂OCHF₂, —CH₂C(CH₃)₂OCH₃,        CH₂C(CH₃)₂CH₂NH₂, —CH₂CHFC(O)NHCH(CH₃)₂, —CH₂CH₂NHS(O)₂CH₃, or        —CH₂CH₂NHC(O)OC(CH₃)₂CF₃; (ii) —CH₂(azetidinyl),        —CH₂(cyclopropyl), CH₂(fluorocyclobutyl),        —CH₂(hydroxycyclobutyl), —CH₂(oxetanyl), CH₂(methyloxetanyl),        —CH₂(oxazolyl), —CH₂(methylpyridinyl), CH₂(tetrahydropyranyl),        —CH₂CH₂(methylmorpholinyl) —CH(CH₃)(cyclopropyl),        CH₂CH₂(morpholinyl), —CH₂CH(CH₃)(morpholinyl), or        —CH₂C(CH₃)₂(morpholinyl); (iii) C₃₋₆ cycloalkyl substituted with        zero to 3 substituents independently selected from F, —OH, —CH₃,        —CH₂OH, —C(CH₃)₂OH, —C(O)NH₂, —C(O)NHCH(CH₃)₂, —NH₂, —NHCH₂CF₃,        —NH(oxetanyl), —NHC(O)CHF₂, —NHC(O)(cyclopropyl),        NHC(O)(fluorophenyl), and imidazolyl; azetidinyl substituted        with —C(O)CH₃, C(O)OCH₃, —C(O)OCH₂CH₃, —C(O)OC(CH₃)₃, —S(O)₂CH₃,        fluoropyrimidinyl, or chloropyrimidinyl; tetrahydrofuranyl        substituted with zero to 2 substituents independently selected        from F and —OH; pyrrolidinyl substituted with zero to 1        substituent selected from —C(O)CH₃, —C(O)CH₂CF₃, —C(O)CH₂CN,        —C(O)OCH₃, —S(O)₂CH₃, —C(O)(difluorophenyl), pyrimidinyl,        fluoropyrimidinyl, and methoxypyrimidinyl; piperidinyl        substituted with —S(O)₂CH₃, phenyl, or fluoropyrimidinyl;        tetrahydropyranyl, fluorotetrahydropyranyl, or oxetanyl; (iv)        adamantanyl, hydroxyadamantanyl, benzo[d]imidazolyl,        benzo[d]oxazolyl, benzo[d]triazolyl, benzothiazolyl,        bicyclo[1.1.1]pentanyl, or hydroxybicyclo[2.2.1]heptanyl; or (v)        phenyl substituted with 1 to 2 substituents independently        selected from F, —OH, —CN, —CH₂OH, —C(CH₃)₂OH, —OCH₃, —C(O)NH₂,        C(O)NHCH₃, —NHC(O)CH₃, —NHC(O)S(O)₂CH₃, —S(O)₂NH₂, pyrazolyl,        methyl pyrazolyl, imidazolyl, triazolyl, methyl tetrazolyl, and        ethyl tetrazolyl; pyrazolyl substituted with 1 to 2 substituents        independently selected from —CH₃, —CH₂CH₃, —CH₂CH₂CH₃,        —CH(CH₃)₂, —CHF₂, —CH₂CHF₂, —CH₂CF₃, —CH₂CHFCH₃, CH₂CH₂CH₂F,        —CH₂C(CH₃)₂F, —CH₂CF₂CH₃, —CH₂C(CH₃)₂OH, —CH₂CH₂OCH₃,        —CH₂CH(CH₃)OCHF₂, —CH₂CH₂CN, —C(O)NHCH₂CH₃, —S(O)₂CH₃,        cyclopropyl, oxetanyl, phenyl, pyrimidinyl, fluoropyrimidinyl,        and tetrahydropyranyl; methyl thiadiazolyl, hydroxypropyl        thiazolyl, or indazolyl.

In any aspect or embodiment described herein, the Het of PTM-IV is aheteroaryl selected from:

In any aspect or embodiment described herein, Q of PTM-IV is selectedfrom:

In any aspect or embodiment described herein, the PTM of PTM-IV isselected from:(R)-6-(5-cyano-1H-indol-1-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-(isopropylamino)nicotinamide(PTM-IV-1);(R)-6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-4-(cyclopropylamino)-N-(2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide(PTM-IV-2);(R)-6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-((tetrahydro-2H-pyran-4-yl)amino)nicotinamide(PTM-IV-3);(R)-6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-4-(ethylamino)-N-(2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide (PTM-IV-4);(R)-6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-(2,2,2-trifluoroethyl)amino)nicotinamide(PTM-IV-5);(R)-6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-4-(cyclobutylamino)-N-(2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide (PTM-IV-6);6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4-((tetrahydro-2H-pyran-3-yl)amino)nicotinamide(PTM-IV-7);6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N—((S)-2-fluoro-3-hydroxy-3-methylbutyl)-4-((tetrahydro-2H-pyran-3-yl)amino)nicotinamide(PTM-IV-8);6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4-(((S)-1-hydroxypropan-2-yl)amino)nicotinamide (PTM-IV-9);(R)-6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-4-(cyclopentylamino)-N-(2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide(PTM-IV-10);6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-(3-hydroxy-3-methylbutyl)-4-(isopropylamino)nicotinamide(PTM-IV-11);6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-(3-hydroxy-3-methylbutyl)-4-((tetrahydro-2H-pyran-4-yl)amino)nicotinamide(PTM-IV-12);4-((1s,3S)-adamantan-1-ylamino)-6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide(PTM-IV-13);6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-(4-hydroxybicyclo[2.2.1]heptan-1-yl)-4-(isopropylamino)nicotinamide(PTM-IV-14);N-(3-(tert-butoxy)propyl)-6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-4-(isopropylamino)nicotinamide(PTM-IV-15);(R)-6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-((4-hydroxybicyclo[2.2.1]heptan-1-yl)amino)nicotinamide(PTM-IV-16);(R)-6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-((1-methylcyclopropyl)amino)nicotinamide(PTM-IV-17);(R)-6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-((1-methylcyclopropyl)amino)nicotinamide(PTM-IV-18);(R)-6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-(isopentylamino)nicotinamide (19);(R)-6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-(((3-methyloxetan-3-yl)methyl)amino)nicotinamide(PTM-IV-20);6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4-((4-hydroxybutan-2-yl)amino)nicotinamide(PTM-IV-21);6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N—((S)-2-fluoro-3-hydroxy-3-methylbutyl)-4-((4-hydroxybutan-2-yl)amino)nicotinamide(PTM-IV-22);(S)-6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-(isopropylamino)nicotinamide(PTM-IV-23);6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4-((3-hydroxycyclopentyl)amino)nicotinamide(PTM-IV-24); diastereomer 1;6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4-((3-hydroxycyclopentyl)amino)nicotinamide(PTM-IV-25); diastereomer 2;6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4-((3-hydroxycyclopentyl)amino)nicotinamide(PTM-IV-26); diastereomer 3;6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4-((3-hydroxycyclopentyl)amino)nicotinamide(PTM-IV-27); diastereomer 4;(R)-6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-(((1-hydroxycyclobutyl)methyl)amino)nicotinamide(PTM-IV-28);(R)-6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-((oxetan-3-ylmethyl)amino)nicotinamide (29);6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4-(((1R,2R)-2-hydroxycyclopentyl)amino)nicotinamide(PTM-IV-30);(R)-6-(5-chloro-1H-pyrrolo[2,3-b]pyridin-1-yl)-4-(cyclobutylamino)-N-(2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide(PTM-IV-31);(R)-6-(5-chloro-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-((tetrahydro-2H-pyran-4-yl)amino)nicotinamide (PTM-IV-32);(R)-6-(5-chloro-1H-pyrrolo[2,3-b]pyridin-1-yl)-4-(ethylamino)-N-(2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide(PTM-IV-33);(R)-6-(5-chloro-1H-pyrrolo[2,3-b]pyridin-1-yl)-4-(cyclopropylamino)-N-(2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide(PTM-IV-34);(R)-6-(5-chloro-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-((2-hydroxy-2-methylpropyl)amino)nicotinamide(PTM-IV-35);6-(5-chloro-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-(3-hydroxy-3-methylbutyl)-4-((tetrahydro-2H-pyran-4-yl)amino)nicotinamide(PTM-IV-36);(R)-6-(5-chloro-1H-indol-1-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-(isopropylamino)nicotinamide(PTM-IV-37);(R)-6-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-(isopropylamino)nicotinamide(PTM-IV-38);(R)—N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-(isopropylamino)-6-(7H-pyrrolo[2,3-d]pyrimidin-7-yl)nicotinamide(PTM-IV-39);(R)—N-(2-fluoro-3-hydroxy-3-methylbutyl)-6-(7H-pyrrolo[2,3-d]pyrimidin-7-yl)-4-((tetrahydro-2H-pyran-4-yl)amino)nicotinamide(PTM-IV-40);(R)-4-(cyclopropylamino)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-6-(7H-pyrrolo[2,3-d]pyrimidin-7-yl)nicotinamide(PTM-IV-41);(R)—N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-((2-hydroxy-2-methylpropyl)amino)-6-(7H-pyrrolo[2,3-d]pyrimidin-7-yl)nicotinamide(PTM-IV-42);N-(3-hydroxy-3-methylbutyl)-6-(7H-pyrrolo[2,3-d]pyrimidin-7-yl)-4-((tetrahydro-2H-pyran-4-yl)amino)nicotinamide(PTM-IV-43);N-(3-hydroxy-3-methylbutyl)-4-(isopropylamino)-6-(7H-pyrrolo[2,3-d]pyrimidin-7-yl)nicotinamide(PTM-IV-44);(R)-6-(5-acetamido-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-(isopropylamino)nicotinamide(PTM-IV-45);(R)-6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-((3-hydroxyphenyl)amino)nicotinamide(PTM-IV-46);6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-(3-isopropoxypropyl)-4-(isopropylamino)nicotinamide (PTM-IV-47);6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-((2R)-2-fluoro-3-hydroxybutyl)-4-(isopropylamino)nicotinamide(PTM-IV-48);6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-((2S)-2-fluoro-3-hydroxybutyl)-4-(isopropylamino)nicotinamide(PTM-IV-49);(R)-6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-((3-sulfamoylphenyl)amino)nicotinamide(PTM-IV-50);(R)-6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-((3-methoxyphenyl)amino)nicotinamide(PTM-IV-51);6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4-(((R)-2-fluoro-3-hydroxy-3-methylbutyl)amino)nicotinamide(PTM-IV-52);(R)-6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-4-((3,3-difluorocyclobutyl)amino)-N-(2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide(PTM-IV-53);(R)-4-((3-acetamidophenyl)amino)-6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide (PTM-IV-54);(R)-6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-((3-(methylcarbamoyl)phenyl)amino)nicotinamide(PTM-IV-55);(R)-4-((3-carbamoylphenyl)amino)-6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide(PTM-IV-56);(R)-6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-((3-(methylsulfonamido)phenyl)amino)nicotinamide (PTM-IV-57);6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-4-(isopropylamino)-N-(4-sulfamoylphenethyl)nicotinamide(PTM-IV-58);(R)-6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-((3-(2-hydroxypropan-2-yl)phenyl)amino)nicotinamide (PTM-IV-59);(R)-4-((4-carbamoylphenyl)amino)-6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide(PTM-IV-60);6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4-(((1s,4S)-4-hydroxy-4-methylcyclohexyl)amino)nicotinamide(PTM-IV-61);6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4-(((trans)-4-hydroxy-4-methylcyclohexyl)amino)nicotinamide(PTM-IV-62);6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-4-(isopropylamino)-N-(2-(methylsulfonamido)ethyl)nicotinamide(PTM-IV-63);(R)-4-(benzo[d]thiazol-6-ylamino)-6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide(PTM-IV-64);(R)-6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-(((1-fluorocyclobutyl)methyl)amino)nicotinamide (PTM-IV-65);(R)-6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-4-((3-cyanophenyl)amino)-N-(2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide(PTM-IV-66);(R)-4-((4-(1H-1,2,4-triazol-1-yl)phenyl)amino)-6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide(PTM-IV-67);(R)-6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-((4-(1-methyl-1H-tetrazol-5-yl)phenyl)amino)nicotinamide(PTM-IV-68);(R)-6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-((4-(1-methyl-1H-tetrazol-5-yl)phenyl)amino)nicotinamide(PTM-IV-69);6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-(2-(1,1-dioxidotetrahydrothiophen-3-yl)amino)-2-oxoethyl)-4-(isopropylamino)nicotinamide(PTM-IV-70);(R)-6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-((3-(hydroxymethyl)phenyl)amino)nicotinamide(PTM-IV-71);6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4-(((2S)-3-fluorobutan-2-yl)amino)nicotinamide (PTM-IV-72);N-(2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)-6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-4-(isopropylamino)nicotinamide(PTM-IV-73);(R)—N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-(isopropylamino)-6-(1H-pyrrolo[2,3-b]pyridin-1-yl)nicotinamide(PTM-IV-74);(R)-6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-(isopropylamino)nicotinamide(PTM-IV-75);(R)-6-(5-chloro-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-(isopropylamino)nicotinamide (PTM-IV-76);(R)-6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-((2-hydroxy-2-methylpropyl)amino)nicotinamide(PTM-IV-77);6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4-((1-fluoropropan-2-yl)amino)nicotinamide(PTM-IV-78);6-(5-cyano-1H-indol-1-yl)-4-(isopropylamino)-N-((trans)-4-(methylcarbamoyl)cyclohexyl)nicotinamide(PTM-IV-79);6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-4-(isopropylamino)-N-((trans)-4-(methylcarbamoyl)cyclohexyl)nicotinamide(PTM-IV-80);4-(isopropylamino)-N-((trans)-4-(methylcarbamoyl)cyclohexyl)-6-(7H-pyrrolo[2,3-d]pyrimidin-7-yl)nicotinamide(PTM-IV-81);N-((trans)-4-(methylcarbamoyl)cyclohexyl)-6-(7H-pyrrolo[2,3-d]pyrimidin-7-yl)-4-((tetrahydro-2H-pyran-4-yl)amino)nicotinamide(PTM-IV-82);N-((trans)-4-acetamidocyclohexyl)-6-(7H-pyrrolo[2,3-d]pyrimidin-7-yl)-4-((tetrahydro-2H-pyran-4-yl)amino)nicotinamide(PTM-IV-83);N-((trans)-4-acetamidocyclohexyl)-4-(isopropylamino)-6-(7H-pyrrolo[2,3-d]pyrimidin-7-yl)nicotinamide(PTM-IV-84);6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-4-(cyclopropylamino)-N-((trans)-4-(methylcarbamoyl)cyclohexyl)nicotinamide (PTM-IV-85);6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-((trans)-4-(methylcarbamoyl)cyclohexyl)-4-((tetrahydro-2H-pyran-4-yl)amino)nicotinamide(PTM-IV-86);N-((trans)-4-acetamidocyclohexyl)-6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-4-(cyclopropylamino)nicotinamide(PTM-IV-87);N-((trans)-4-acetamidocyclohexyl)-6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-4-((tetrahydro-2H-pyran-4-yl)amino)nicotinamide(PTM-IV-88);6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-4-(((S)-1-hydroxypropan-2-yl)amino)-N-((1r,4S)-4-(methylcarbamoyl)cyclohexyl)nicotinamide(PTM-IV-89);6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-4-(isopropylamino)-N-((trans)-4-(isopropylcarbamoyl)cyclohexyl)nicotinamide (PTM-IV-90);6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-((trans)-4-(cyclopropylcarbamoyl)cyclohexyl)-4-(isopropylamino)nicotinamide(PTM-IV-91);6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-((trans)-4-(ethylcarbamoyl)cyclohexyl)-4-(isopropylamino)nicotinamide(PTM-IV-92);6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-4-((2-hydroxy-2-methylpropyl)amino)-N-((trans)-4-(methylcarbamoyl)cyclohexyl)nicotinamide (PTM-IV-93);6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-4-((2-hydroxy-2-methylpropyl)amino)-N-((trans)-4-((²H₃)methylcarbamoyl)cyclohexyl)nicotinamide(PTM-IV-94);6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-4-(isopropylamino)-N-((trans)-4-nitrocyclohexyl)nicotinamide(PTM-IV-95);6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-((trans)-4-(2-hydroxypropan-2-yl)cyclohexyl)-4-(isopropylamino)nicotinamide(PTM-IV-96);methyl((trans)-4-(6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-4-(isopropylamino)nicotinamido)cyclohexyl)carbamate (PTM-IV-97);6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-((trans)-4-hydroxycyclohexyl)-4-(isopropylamino)nicotinamide(PTM-IV-98);6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-((trans)-4-hydroxy-4-methylcyclohexyl)-4-(isopropylamino)nicotinamide(PTM-IV-99);6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-4-(ethylamino)-N-((trans)-4-(2-hydroxypropan-2-yl)cyclohexyl)nicotinamide(PTM-IV-100);6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-4-(isopropylamino)-N-((trans)-4-(methylthio)cyclohexyl)nicotinamide(PTM-IV-101);6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-4-(isopropylamino)-N-((trans)-4-(methylsulfonyl)cyclohexyl)nicotinamide(PTM-IV-102);6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-((trans)-4-(methylsulfonyl)cyclohexyl)-4-((tetrahydro-2H-pyran-4-yl)amino)nicotinamide(PTM-IV-103);6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-4-(cyclopropylamino)-N-((trans)-4-(methylsulfonyl)cyclohexyl)nicotinamide (PTM-IV-104);4-((3-carbamoylphenyl)amino)-6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-((trans)-4-(methylsulfonyl)cyclohexyl)nicotinamide(PTM-IV-105);6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4-((3-fluorotetrahydro-2H-pyran-4-yl)amino)nicotinamide(PTM-IV-106);6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4-((3-fluorotetrahydro-2H-pyran-4-yl)amino)nicotinamide(PTM-IV-107);6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N—((S)-2-fluoro-3-hydroxy-3-methylbutyl)-4-((3-fluorotetrahydro-2H-pyran-4-yl)amino)nicotinamide (PTM-IV-108);6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4-((3-fluorocyclopentyl)amino)nicotinamide(PTM-IV-109);6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N—((S)-2-fluoro-3-hydroxy-3-methylbutyl)-4-((3-fluorocyclopentyl)amino)nicotinamide(PTM-IV-110);6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-4-((3,3-difluoro-2-hydroxycyclohexyl)amino)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide (PTM-IV-111);6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-4-((3,3-difluoro-2-hydroxycyclohexyl)amino)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide(PTM-IV-112);N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4-((1-fluoropropan-2-yl)amino)-6-(7H-pyrrolo[2,3-d]pyrimidin-7-yl)nicotinamide(PTM-IV-113);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4-(((R)-1-fluoropropan-2-yl)amino)nicotinamide (PTM-IV-114);N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4-(((R)-1-fluoropropan-2-yl)amino)-6-(7H-pyrrolo[2,3-d]pyrimidin-7-yl)nicotinamide(PTM-IV-115);N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4-(((S)-1-fluoropropan-2-yl)amino)-6-(7H-pyrrolo[2,3-d]pyrimidin-7-yl)nicotinamide(PTM-IV-116);6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4-(((S)-1-fluoropropan-2-yl)amino)nicotinamide(PTM-IV-117);6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4-(((R)-1-fluoropropan-2-yl)amino)nicotinamide(PTM-IV-118);(S)-6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-4-((1-fluoropropan-2-yl)amino)-N-(3-hydroxy-3-methylbutyl)nicotinamide(PTM-IV-119);(R)-6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-4-((1-fluoropropan-2-yl)amino)-N-(3-hydroxy-3-methylbutyl)nicotinamide(PTM-IV-120);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4-(((S)-1-fluoropropan-2-yl)amino)nicotinamide (PTM-IV-121);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-(((S)-1-fluoropropan-2-yl)amino)-N-((1r,4S)-4-(methylcarbamoyl)cyclohexyl)nicotinamide(PTM-IV-122);(R)-1-(4-(ethylamino)-5-(2-fluoro-3-hydroxy-3-methylbutyl)carbamoyl)pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide(PTM-IV-123);(R)-1-(4-(cyclobutylamino)-5-((2-fluoro-3-hydroxy-3-methylbutyl)carbamoyl)pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide(PTM-IV-124);1-((2-(6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-4-(isopropylamino)nicotinamido)ethyl)amino)-2-methyl-1-oxopropan-2-yl acetate(PTM-IV-125);6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-(2-(2-hydroxy-2-methylpropanamido)ethyl)-4-(isopropylamino)nicotinamide(PTM-IV-126);(R)-6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-(2-fluoro-3-methoxypropyl)-4-(isopropylamino)nicotinamide(PTM-IV-127);(R)-6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(2-fluoro-3-methoxypropyl)-4-(isopropylamino)nicotinamide (PTM-IV-128);6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-((2R)-2-fluoro-3-(isopropylamino)butyl)-4-(isopropylamino)nicotinamide(PTM-IV-129);6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-((2R)-2-fluoro-3-(isopropylamino)butyl)-4-(isopropylamino)nicotinamide (PTM-IV-130);6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4-((1-fluoro-3-hydroxypropan-2-yl)amino)nicotinamide(PTM-IV-131);(R)-6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-4-(cyclopropylamino)-N-(2-fluoro-3-(methylamino)-3-oxopropyl)nicotinamide(PTM-IV-132);(R)-6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-(isopropylamino)nicotinamide(PTM-IV-133);(R)-4-(cyclopropylamino)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-6-(1H-pyrazolo[3,4-d]pyrimidin-1-yl)nicotinamide(PTM-IV-134);(R)-6-(5-chloro-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-((tetrahydro-2H-pyran-4-yl)amino)nicotinamide (PTM-IV-135);(R)-6-(5-chloro-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-(cyclopropylamino)-N-(2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide(PTM-IV-136);(R)-6-(5-chloro-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-(isopropylamino)nicotinamide(PTM-IV-137);(R)-6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-(ethylamino)-N-(2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide(PTM-IV-138);(R)-6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-(cyclopropylamino)-N-(2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide(PTM-IV-139);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-(cyclopropylamino)-N-((trans)-4-(methylcarbamoyl)cyclohexyl)nicotinamide(PTM-IV-140);(R)-6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-((tetrahydro-2H-pyran-4-yl)amino)nicotinamide(PTM-IV-141);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4-((tetrahydro-2H-pyran-3-yl)amino)nicotinamide,diastereomer 1 (PTM-IV-142);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N—((S)-2-fluoro-3-hydroxy-3-methylbutyl)-4-((tetrahydro-2H-pyran-3-yl)amino)nicotinamide, diastereomer 2 (PTM-IV-143);(R)—N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-(isopropylamino)-6-(1H-pyrazolo[3,4-d]pyrimidin-1-yl)nicotinamide(PTM-IV-144);(R)-6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-(cyclobutylamino)-N-(2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide(PTM-IV-145);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(3-hydroxy-3-methylbutyl)-4-(isopropylamino)nicotinamide(PTM-IV-146);(R)-6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-(2,2,2-trifluoroethyl)amino)nicotinamide(PTM-IV-147);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-((trans)-4-(2-hydroxypropan-2-yl)cyclohexyl)-4-(isopropylamino)nicotinamide(PTM-IV-148);(R)—N-(3-ethyl-2-fluoro-3-hydroxypentyl)-4-(isopropylamino)-6-(1H-pyrazolo[3,4-d]pyrimidin-1-yl)nicotinamide(PTM-IV-149);6-(5-chloro-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-((trans)-4-(2-hydroxypropan-2-yl)cyclohexyl)-4-(isopropylamino)nicotinamide(PTM-IV-150);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(3-hydroxy-3-methylbutyl)-4-((tetrahydro-2H-pyran-4-yl)amino)nicotinamide(PTM-IV-151);6-(5-chloro-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-(isopropylamino)-N-((trans)-4-(methylcarbamoyl)cyclohexyl)nicotinamide(PTM-IV-152);(R)—N-(2-fluoro-3-hydroxy-3-methylbutyl)-6-(5-hydroxy-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-(isopropylamino)nicotinamide(PTM-IV-153);6-(5-chloro-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-(isopropylamino)-N-(2-morpholinoethyl)nicotinamide(PTM-IV-154);(R)—N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-(isopropylamino)-6-(5-methyl-1H-pyrazolo[3,4-b]pyridin-1-yl)nicotinamide(PTM-IV-155);(R)-4-(cyclopropylamino)-6-(5-fluoro-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide(PTM-IV-156);(R)-6-(5-fluoro-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-(isopropylamino)nicotinamide (PTM-IV-157);(R)-6-(5-bromo-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-(isopropylamino)nicotinamide(PTM-IV-158);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4-(((trans)-4-hydroxycyclohexyl)amino)nicotinamide(PTM-IV-159);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-(isopropylamino)-N-((trans)-4-(methylcarbamoyl)cyclohexyl)nicotinamide(PTM-IV-160);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-(isopropylamino)-N-((trans)-4-(methylsulfonyl)cyclohexyl)nicotinamide(161);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-(isopropylamino)-N-((trans)-4-((²H3)methylcarbamoyl)cyclohexyl)nicotinamide(PTM-IV-162);(R)-6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-((4-fluorocyclohexyl)amino)nicotinamide(PTM-IV-163);N-((trans)-4-acetamidocyclohexyl)-6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-(isopropylamino)nicotinamide (PTM-IV-164);N-(2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)-6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-(isopropylamino)nicotinamide(PTM-IV-165);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-(isopropylamino)-N-((trans)-4-(methylsulfonamido)cyclohexyl)nicotinamide(PTM-IV-166);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(2,2-difluoro-3-hydroxy-3-methylbutyl)-4-(isopropylamino)nicotinamide(PTM-IV-167);(R)—N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-(isopropylamino)-6-(3-(pyridazin-4-yl)-1H-pyrazol-1-yl)nicotinamide(PTM-IV-168);(R)-6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-(2,2-difluoro-3-hydroxy-3-methylbutyl)amino)-N-(2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide (PTM-IV-169);(R)—N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-(isopropylamino)-6-(9H-purin-9-yl)nicotinamide(PTM-IV-170);(R)-6-(2-amino-9H-purin-9-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-(isopropylamino)nicotinamide(PTM-IV-171);(R)—N-(2-fluoro-3-hydroxy-3-methylbutyl)-6-(2-((2-hydroxyethyl)amino)-9H-purin-9-yl)-4-(isopropylamino)nicotinamide(PTM-IV-172);6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-((1s,4s)-4-hydroxy-4-((1-methyl-1H-pyrazol-5-yl)cyclohexyl)-4-(isopropylamino)nicotinamide (PTM-IV-173);6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-((1s,4s)-4-fluoro-4-((1-methyl-1H-pyrazol-5-yl)cyclohexyl)-4-(isopropylamino)nicotinamide(PTM-IV-174);6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-((1s,4s)-4-hydroxy-4-(thiazol-2-yl)cyclohexyl)-4-(isopropylamino)nicotinamide(PTM-IV-175);6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-((1s,4s)-4-hydroxy-4-((1-methyl-1H-imidazol-2-yl)cyclohexyl)-4-(isopropylamino)nicotinamide (PTM-IV-176);6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-((1s,4s)-4-hydroxy-4-(pyridin-3-yl)cyclohexyl)-4-(isopropylamino)nicotinamide(PTM-IV-177);6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-((1s,4s)-4-hydroxy-4-(pyridin-2-yl)cyclohexyl)-4-(isopropylamino)nicotinamide(PTM-IV-178);6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-((1s,4s)-4-hydroxy-4-(pyridin-4-yl)cyclohexyl)-4-(isopropylamino)nicotinamide(PTM-IV-179);6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-((1s,4s)-4-fluoro-4-(thiazol-2-yl)cyclohexyl)-4-(isopropylamino)nicotinamide(PTM-IV-180);6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-((1s,4s)-4-fluoro-4-((1-methyl-1H-imidazol-2-yl)cyclohexyl)-4-(isopropylamino)nicotinamide (PTM-IV-181);6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-((trans)-4-fluoro-4-((1-methyl-1H-imidazol-2-yl)cyclohexyl)-4-(isopropylamino)nicotinamide(PTM-IV-182);6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-(2,4-dioxo-1,3-diazaspiro[4.5]decan-8-yl)-4-(isopropylamino)nicotinamide(PTM-IV-183);(S)-6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-4-(isopropylamino)-N-(4-(pyridin-4-yl)cyclohex-3-en-1-yl)nicotinamide(PTM-IV-184);(R)-6-(2-(dimethylamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-(isopropylamino)nicotinamide(PTM-IV-185);(R)-6-(2-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-(isopropylamino)nicotinamide (PTM-IV-186);(R)—N-(2-fluoro-3-hydroxy-3-methylbutyl)-6-(2-(2-hydroxy-2-methylpropyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-4-(isopropylamino)nicotinamide(PTM-IV-187);(R)—N-(2-fluoro-3-hydroxy-3-methylbutyl)-6-(2-((2-hydroxyethyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-4-(isopropylamino)nicotinamide(PTM-IV-188);N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)-6-(2-((S)-3-hydroxypyrrolidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-4-(isopropylamino)nicotinamide(PTM-IV-189);N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)-6-(2-((R)-3-hydroxypyrrolidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-4-(isopropylamino)nicotinamide(PTM-IV-190);(R)-4-(6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-(isopropylamino)nicotinamido)-3-fluoro-2-methylbutan-2-yldihydrogen phosphate (PTM-IV-191);R)-6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-(isopropylamino)nicotinamide,hydrochloride (PTM-IV-192);(R)-4-(sec-butylamino)-6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(3-hydroxy-3-methylbutyl)nicotinamide (PTM-IV-193);(R)—N-(2-fluoro-3-hydroxy-3-methylbutyl)-6-(5-hydroxy-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-(isopropylamino)nicotinamide(PTM-IV-194);(R)—N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-(isopropylamino)-6-(5-methoxy-1H-pyrazolo[3,4-b]pyridin-1-yl)nicotinamide(PTM-IV-195);(S)-6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-(isopropylamino)nicotinamide(PTM-IV-196);(R)-6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(2-fluoro-3-(isopropylamino)-3-oxopropyl)-4-(isopropylamino)nicotinamide(PTM-IV-197);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-(isopropylamino)-N-(4-methoxycyclohexyl)nicotinamide(PTM-IV-198);N-butyl-6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-(isopropylamino)nicotinamide(PTM-IV-199);(R)-6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(2-fluoro-3-methoxy-3-methylbutyl)-4-(isopropylamino)nicotinamide (PTM-IV-200);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-(isopropylamino)-N-(3-morpholinopropyl)nicotinamide(PTM-IV-201);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4-(((2S)-3-fluorobutan-2-yl)amino)nicotinamide(202);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4-(((2S)-3-fluorobutan-2-yl)amino)nicotinamide(203);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-(isopropylamino)-N-(2-morpholinoethyl)nicotinamide(204);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4-((4-fluorobutan-2-yl)amino)nicotinamide(205);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-(isopropylamino)-N-(2-morpholino-2-oxoethyl)nicotinamide (206); methyl3-(6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-(isopropylamino)nicotinamido)propanoate(207);diethyl(2-(6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-(isopropylamino)nicotinamido)ethyl)phosphonate(208);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-((1,1-dioxidotetrahydrothiophen-3-yl)methyl)-4-(isopropylamino)nicotinamide(209);(R)-6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(2-fluoro-3-trideuteromethoxy-3-methylbutyl)-4-(isopropylamino)nicotinamide(210);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(2-(1,1-dioxidothiomorpholino)ethyl)-4-(isopropylamino)nicotinamide(211);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(3-(ethylamino)-3-oxopropyl)-4-(isopropylamino)nicotinamide(212);N-(3-(1H-1,2,4-triazol-5-yl)propyl)-6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-(isopropylamino)nicotinamide (213);N-((1R,4R)-4-(2-hydroxypropan-2-yl)cyclohexyl)-4-(isopropylamino)-6-(5-methyl-1H-pyrazolo[3,4-b]pyridin-1-yl)nicotinamide(214);(R)-6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(3-ethoxy-2-fluoro-3-methylbutyl)-4-(isopropylamino)nicotinamide(215);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-(isopropylamino)-N-(6-morpholinopyridin-3-yl)nicotinamide(216);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(5-hydroxypyridin-2-yl)-4-(isopropylamino)nicotinamide(217);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-(isopropylamino)-N-((1R,4R)-4-((2-(methylamino)-2-oxoethyl)cyclohexyl)nicotinamide(218);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-(isopropylamino)-N-(2-(methylsulfonamido)ethyl)nicotinamide(219);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-(isopropylamino)-N-(2-(tetrahydro-2H-pyran-2-yl)ethyl)nicotinamide(220);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-(isopropylamino)-N-(5-morpholinopyridin-2-yl)nicotinamide(221);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-(isopropylamino)-N-(4-morpholinophenyl)nicotinamide(222);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-(isopropylamino)-N-(1H-pyrrolo[2,3-c]pyridin-5-yl)nicotinamide(223);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-(isopropylamino)-N-(2-morpholinopyrimidin-5-yl)nicotinamide(224);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(5-(2-(dimethylamino)ethoxy)pyridin-2-yl)-4-(isopropylamino)nicotinamide(225);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-(isopropylamino)-N-(4-(morpholinomethyl)phenyl)nicotinamide(226);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-(isopropylamino)-N-(6-(piperazin-1-yl)pyridin-3-yl)nicotinamide(227);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(6-(dimethylamino)pyridin-3-yl)-4-(isopropylamino)nicotinamide(228);(R)-6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(2-fluoro-3-(methylamino)-3-oxopropyl)-4-(isopropylamino)nicotinamide(229);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N—((R)-2-fluoro-3-(((S)-1-hydroxypropan-2-yl)amino)-3-oxopropyl)-4-(isopropylamino)nicotinamide (230);(R)-6-(5-(difluoromethyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-(isopropylamino)nicotinamide(231);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-((2R)-2-fluoro-3-hydroxy-4-methylpentyl)-4-(isopropylamino)nicotinamide(232);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-((2R)-2-fluoro-3-hydroxy-4-methylpentyl)-4-(isopropylamino)nicotinamide(233);(R)-6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-((1-hydroxy-2-methylpropan-2-yl)amino)nicotinamide(234);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(2-(4-hydroxytetrahydro-2H-pyran-4-yl)ethyl)-4-(isopropylamino)nicotinamide (235);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(5-(2-hydroxypropan-2-yl)pyridin-2-yl)-4-(isopropylamino)nicotinamide(236);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(2-(3-hydroxytetrahydrofuran-3-yl)ethyl)-4-(isopropylamino)nicotinamide (237);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(3-hydroxybutyl)-4-(isopropylamino)nicotinamide(23.8);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(3-hydroxybutyl)-4-(isopropylamino)nicotinamide(239);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-(isopropylamino)-N-(1-(pyrimidin-2-yl)piperidin-4-yl)nicotinamide(240);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-(isopropylamino)-N-(5-(4-methylpiperazin-1-yl)pyridin-2-yl)nicotinamide(241);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-(isopropylamino)-N-(3-(4-methylpiperazin-1-yl)-3-oxopropyl)nicotinamide (242);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(2-fluoro-2-(3-hydroxyoxetan-3-yl)ethyl)-4-(isopropylamino)nicotinamide,racemic (243); 6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-((1S,3S)-3-(2-hydroxypropan-2-yl)cyclopentyl)-4-(isopropylamino)nicotinamide(244);(R)-6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-(isopropylamino)-N-(1-(methylsulfonyl)piperidin-3-yl)nicotinamide(245);(S)-6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-(isopropylamino)-N-(1-(methylsulfonyl)piperidin-3-yl)nicotinamide (246);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-(isopropylamino)-N-(6-(4-methoxypiperidin-1-yl)pyridin-3-yl)nicotinamide(247);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(2-fluoro-2-(3-hydroxyoxetan-3-yl)ethyl)-4-(isopropylamino)nicotinamide(248);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(2-fluoro-2-(3-hydroxyoxetan-3-yl)ethyl)-4-(isopropylamino)nicotinamide(249);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(2-(4-hydroxy-1-methylpiperidin-4-yl)ethyl)-4-(isopropylamino)nicotinamide(250);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-(isopropylamino)-N-(4-sulfamoylphenethyl)nicotinamide(251);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(2-(1-hydroxycyclopentyl)ethyl)-4-(isopropylamino)nicotinamide(252);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(2-(4-hydroxy-1-(oxetan-3-yl)piperidin-4-yl)ethyl)-4-(isopropylamino)nicotinamide(253);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-(isopropylamino)-N-(5-(4-methoxypiperidin-1-yl)pyridin-2-yl)nicotinamide(254);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(2-(3-hydroxypyrrolidin-3-yl)ethyl)-4-(isopropylamino)nicotinamide(255);(R)-6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(2-fluoro-3-morpholino-3-oxopropyl)-4-(isopropylamino)nicotinamide(256);(R)-6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(2-fluoro-3-(4-(methylsulfonyl)piperazin-1-yl)-3-oxopropyl)-4-(isopropylamino)nicotinamide (257);6-(5-chloro-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(2-fluoro-2-(3-hydroxyoxetan-3-yl)ethyl)-4-(isopropylamino)nicotinamide(258);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-(isopropylamino)-N-(2-(pyridin-4-yl)ethyl)nicotinamide(259);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(4-fluorophenethyl)-4-(isopropylamino)nicotinamide(260);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-(isopropylamino)-N-(4-methoxyphenethyl)nicotinamide(261);(R)-6-(6-amino-5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-(isopropylamino)nicotinamide(262);6-(6-amino-5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-((2-(2-hydroxypropan-2-yl)cyclopropyl)methyl)-4-(isopropylamino)nicotinamide(263);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-(isopropylamino)-N-(3-(methylsulfonamido)butyl)nicotinamide(264);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-(isopropylamino)-N-(3-(methylsulfonamido)butyl)nicotinamide(265);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-(isopropylamino)-N-(2-(1-methylpiperidin-4-yl)ethyl)nicotinamide(266);N-((3-benzyl-1,2,4-oxadiazol-5-yl)methyl)-6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-(isopropylamino)nicotinamide(267);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-(isopropylamino)-N-(1-(oxetan-3-yl)-1H-pyrazol-4-yl)nicotinamide(268);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-(isopropylamino)-N-(4-(N-(methylsulfonyl)methylsulfonamido)phenethyl)nicotinamide(269);N-(4-acetamidophenethyl)-6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-(isopropylamino)nicotinamide (270);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-(isopropylamino)-N-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)nicotinamide(271);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-(isopropylamino)-N-(1-(isopropylsulfonyl)piperidin-4-yl)nicotinamide(272);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(1-isobutyrylpiperidin-4-yl)-4-(isopropylamino)nicotinamide(273);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-((1S,4R)-4-((S)-2-hydroxypropanamido)cyclohexyl)-4-(isopropylamino)nicotinamide(274);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(2-(1-(2-cyanoacetyl)piperidin-4-yl)ethyl)-4-(isopropylamino)nicotinamide(275);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-(isopropylamino)-N-(2-(pyridin-3-yl)ethyl)nicotinamide(276);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(2-(1,4-dihydroxy-4-methylcyclohexyl)ethyl)-4-(isopropylamino)nicotinamide(277);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-(isopropylamino)-N-(1-(1-(methylsulfonyl)azetidine-3-carbonyl)piperidin-4-yl)nicotinamide (278);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(2-(4,4-difluoro-1-hydroxycyclohexyl)ethyl)-4-(isopropylamino)nicotinamide (279);(R)—N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-(isopropylamino)-6-(5-((3-methylbutanamido)methyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)nicotinamide(280);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-(isopropylamino)-N-(1-(1-(methylsulfonyl)azetidin-3-yl)-1H-pyrazol-4-yl)nicotinamide (281);(R)-6-(6-amino-5-chloro-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-(isopropylamino)nicotinamide (282);4-((R)-sec-butylamino)-6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide(283);6-(6-amino-5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-4((S)-sec-butylamino)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide(284);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)-4-(isopropylamino)nicotinamide(285);(R)-4-(tert-butylamino)-6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide(286);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-((1R,4R)-4-((R)-2-hydroxypropanamido)cyclohexyl)-4-(isopropylamino)nicotinamide(287);4-(tert-butylamino)-6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(3-fluoro-3-methylbutyl)nicotinamide(288);4-((S)-sec-butylamino)-6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide(289);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(1-(ethylsulfonyl)piperidin-4-yl)-4-(isopropylamino)nicotinamide (290);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(2-(1-hydroxy-4-methoxycyclohexyl)ethyl)-4-(isopropylamino)nicotinamide(291);(R)-6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-((1-methylcyclopropyl)amino)nicotinamide(292);(R)-6-(6-amino-5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-(tert-butylamino)-N-(2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide (293);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(2-(dihydro-2H-pyran-4(3H)-ylidene)-2-fluoroethyl)-4-(isopropylamino)nicotinamide(294);(R)-6-(6-amino-5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(2,3-difluoro-3-methylbutyl)-4-(isopropylamino)nicotinamide(295);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-((3R,6S)-6-(2-hydroxypropan-2-yl)tetrahydro-2H-pyran-3-yl)-4-(isopropylamino)nicotinamide (296);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4-((1,1,1-trifluoropropan-2-yl)amino)nicotinamide(297);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-isopentyl-4-(isopropylamino)nicotinamide(298);6-(6-amino-5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(2-cyclopropylethyl)-4-(isopropylamino)nicotinamide(299);6-(6-amino-5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-((R)-sec-butylamino)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide(300);6-(6-amino-5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4-((1,1,1-trifluoropropan-2-yl)amino)nicotinamide(301);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(2-cyclopropylethyl)-4-(isopropylamino)nicotinamide(302);6-(6-amino-5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-isopentyl-4-(isopropylamino)nicotinamide(303);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-4-(isopropylamino)nicotinamide(304);6-(6-amino-5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-(isopropylamino)-N-methylnicotinamide(305);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-(isopropylamino)-N-(3-methyl-3-(methylsulfonamido)butyl)nicotinamide(306);6-(6-amino-5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(3-fluoro-3-methylbutyl)-4-(isopropylamino)nicotinamide(307);(R)-6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(2,3-difluoro-3-methylbutyl)-4-(isopropylamino)nicotinamide(308);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-(isopropylamino)-N-(1-(N-isopropylsulfamoyl)piperidin-4-yl)nicotinamide(309);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-(isopropylamino)-N-(2-(tetrahydro-2H-pyran-4-yl)ethyl)nicotinamide(310);N-(2-(1H-imidazol-4-yl)ethyl)-6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-(isopropylamino)nicotinamide (311);(S)-6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(2-fluoro-3-methylbutyl)-4-(isopropylamino)nicotinamide(312);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-(isopropylamino)-N-(1-(N-methylsulfamoyl)piperidin-4-yl)nicotinamide(313);(R)-6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(3-(difluoromethoxy)-2-fluoro-3-methylbutyl)-4-(isopropylamino)nicotinamide(314);(R)-6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(3,3-dicyclopropyl-2-fluoro-3-hydroxypropyl)-4-(isopropylamino)nicotinamide (315);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-(isopropylamino)-N-((1R,4R)-4-(methylcarbamoyl)cyclohexyl)nicotinamide(316);N-((1R,4R)-4-acetamidocyclohexyl)-6-(6-amino-5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-(isopropylamino)nicotinamide(317);(S)-6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(2-cyclopropylethyl)-4-((1-hydroxypropan-2-yl)amino)nicotinamide(318);(S)—N-butyl-6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-((1-hydroxypropan-2-yl)amino)nicotinamide (319);(S)-6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-((1-hydroxypropan-2-yl)amino)-N-isopentylnicotinamide(320);(R)-6-(6-amino-5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(2-fluoro-3-methoxy-3-methylbutyl)-4-(isopropylamino)nicotinamide (321);6-(6-amino-5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-(isopropylamino)-N-(1-methylcyclopropyl)nicotinamide(322);(R)-6-(6-amino-5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(1-cyclopropylethyl)-4-(isopropylamino)nicotinamide(323);6-(6-amino-5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-cyclohexyl-4-(isopropylamino)nicotinamide(324);6-(6-amino-5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(1-cyanocyclopropyl)-4-(isopropylamino)nicotinamide(325);6-(6-amino-5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-(isopropylamino)-N-propylnicotinamide(326);6-(6-amino-5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(cyclopent-2-en-1-yl)-4-(isopropylamino)nicotinamide(327);(R)-6-(6-amino-5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(2-fluoropropyl)-4-(isopropylamino)nicotinamide(328);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(2-fluoro-2-(tetrahydro-2H-pyran-4-yl)ethyl)-4-(isopropylamino)nicotinamide(329);(R)-6-(5-chloro-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(2,3-difluoro-3-methylbutyl)-4-(isopropylamino)nicotinamide(330);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(2-(1-hydroxycyclopropyl)ethyl)-4-(isopropylamino)nicotinamide (331);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(3,3-difluorobutyl)-4-(isopropylamino)nicotinamide(332);(R)-6-(6-cyano-3H-imidazo[4,5-b]pyridin-3-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-(oxetan-3-ylamino)nicotinamide(333);N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)-6-(2-(((R)-2-fluoro-3-hydroxy-3-methylbutyl)amino)-9H-purin-9-yl)-4-(isopropylamino)nicotinamide(334);(R)-6-(6-cyano-3H-imidazo[4,5-b]pyridin-3-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-(isopropylamino)nicotinamide (335);(R)-6-(6-cyano-3H-imidazo[4,5-b]pyridin-3-yl)-4-(cyclopropylamino)-N-(2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide(336);(R)-6-(6-cyano-3H-imidazo[4,5-b]pyridin-3-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-(propylamino)nicotinamide(337);(R)-6-(6-cyano-3H-imidazo[4,5-b]pyridin-3-yl)-4-(cyclobutylamino)-N-(2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide(338);(R)-6-(6-chloro-3H-imidazo[4,5-b]pyridin-3-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-(isopropylamino)nicotinamide(339);(R)-6-(6-chloro-3H-imidazo[4,5-b]pyridin-3-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-(oxetan-3-ylamino)nicotinamide(340);(R)-6-(5-amino-6-cyano-3H-imidazo[4,5-b]pyridin-3-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-(isopropylamino)nicotinamide(341);(R)-6-(6-cyano-3H-imidazo[4,5-b]pyridin-3-yl)-N-(2,3-difluoro-3-methylbutyl)-4-(isopropylamino)nicotinamide(342);(R)-6-(6-cyano-3H-imidazo[4,5-b]pyridin-3-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-((1-methylcyclopropyl)amino)nicotinamide(343);(R)-6-(6-cyano-3H-imidazo[4,5-b]pyridin-3-yl)-N-(2,3-difluoro-3-methylbutyl)-4-(oxetan-3-ylamino)nicotinamide(344);(R)-6-(6-cyano-3H-imidazo[4,5-b]pyridin-3-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-((tetrahydro-2H-pyran-4-yl)amino)nicotinamide(345);(R)-6-(2-amino-9H-purin-9-yl)-N-(2,3-difluoro-3-methylbutyl)-4-(isopropylamino)nicotinamide(346);(R)-6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-((1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)amino)-N-(2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide(347);(R)-6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-((1-(oxetan-3-yl)-1H-pyrazol-4-yl)amino)nicotinamide(348);(R)-6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-((1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)amino)nicotinamide(349);(R)-6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-((1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)amino)nicotinamide(350);(R)-6-(5-chloro-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-((1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)amino)-N-(2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide (351);(R)-6-(5-chloro-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-((1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)amino)nicotinamide (352);(R)-6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)amino)nicotinamide(353);(R)-6-(5-chloro-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)amino)nicotinamide(354);(R)-6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-((1-ethyl-1H-pyrazol-4-yl)amino)-N-(2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide(355);(R)-6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-((1-(2-fluoro-2-methylpropyl)-1H-pyrazol-4-yl)amino)-N-(2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide(356);(R)-6-(5-chloro-1H-pyrazolo[3,4-b]pyridin-1-yl)-4((1-ethyl-1H-pyrazol-4-yl)amino)-N-(2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide (357);(R)-6-(5-chloro-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-((1-isopropyl-1H-pyrazol-4-yl)amino)nicotinamide(358);(R)-6-(6-chloro-3H-imidazo[4,5-b]pyridin-3-yl)-4-((1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)amino)-N-(2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide(359);(R)-6-(6-chloro-3H-imidazo[4,5-b]pyridin-3-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)amino)nicotinamide(360);(R)-6-(6-chloro-3H-imidazo[4,5-b]pyridin-3-yl)-4-((1-ethyl-1H-pyrazol-4-yl)amino)-N-(2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide(361);(R)-6-(6-chloro-3H-imidazo[4,5-b]pyridin-3-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-((1-isopropyl-1H-pyrazol-4-yl)amino)nicotinamide(362);(R)-6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-((1-(2-methoxyethyl)-1H-pyrazol-4-yl)amino)nicotinamide(363);(R)-6-(5-chloro-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-((1-(2-methoxyethyl)-1H-pyrazol-4-yl)amino)nicotinamide(364);(R)-6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-((1-(2,2-difluoropropyl)-1H-pyrazol-4-yl)amino)-N-(2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide(365);(R)-6-(6-chloro-3H-imidazo[4,5-b]pyridin-3-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-((1-(2-methoxyethyl)-1H-pyrazol-4-yl)amino)nicotinamide(366);(R)-6-(5-chloro-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-((1-(3-fluoropropyl)-1H-pyrazol-4-yl)amino)nicotinamide (367);(R)-6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-((1-(3-fluoropropyl)-1H-pyrazol-4-yl)amino)nicotinamide(368);(R)-6-(5-chloro-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-((1-(2,2-difluoropropyl)-1H-pyrazol-4-yl)amino)-N-(2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide(369);(R)-6-(6-chloro-3H-imidazo[4,5-b]pyridin-3-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-((1-(3-fluoropropyl)-1H-pyrazol-4-yl)amino)nicotinamide(370);(R)-6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)amino)nicotinamide(371);(R)-6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-4-((1-ethyl-1H-pyrazol-4-yl)amino)-N-(2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide (372);(R)-6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-((1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)amino)nicotinamide (373);(R)-6-(6-chloro-3H-imidazo[4,5-b]pyridin-3-yl)-4-((1-(2-cyanoethyl)-1H-pyrazol-4-yl)amino)-N-(2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide(374);(R)-6-(6-cyano-3H-imidazo[4,5-b]pyridin-3-yl)-4-((1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)amino)-N-(2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide(375);(R)-6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-((1-(2-cyanoethyl)-1H-pyrazol-4-yl)amino)-N-(2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide(376);(R)-6-(5-chloro-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-((1-(2-cyanoethyl)-1H-pyrazol-4-yl)amino)-N-(2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide(377);6-(6-cyano-3H-imidazo[4,5-b]pyridin-3-yl)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4-((1-(2-fluoropropyl)-1H-pyrazol-4-yl)amino)nicotinamide,racemic (378);6-(6-cyano-3H-imidazo[4,5-b]pyridin-3-yl)-4-((1-(2-(difluoromethoxy)propyl)-1H-pyrazol-4-yl)amino)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide(379);(R)-6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-((1-propyl-1H-pyrazol-4-yl)amino)nicotinamide(380);(R)-6-(5-chloro-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4((1-propyl-1H-pyrazol-4-yl)amino)nicotinamide(381);(R)-6-(6-chloro-3H-imidazo[4,5-b]pyridin-3-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-((1-propyl-1H-pyrazol-4-yl)amino)nicotinamide(382);(R)-6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-((1-propyl-1H-pyrazol-4-yl)amino)nicotinamide(383);(R)-4-((1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)amino)-6-(5-fluoro-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide(384);(R)-6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-((1-(methylsulfonyl)-1H-pyrazol-4-yl)amino)nicotinamide(385);(R)-6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-((1-(ethylcarbamoyl)-1H-pyrazol-4-yl)amino)-N-(2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide(386);(R)-6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-((1-methyl-1H-pyrazol-4-yl)amino)nicotinamide(387);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-((1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)amino)-N-isopropylnicotinamide(388);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-((1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)amino)-N-propylnicotinamide(389);N-(tert-butyl)-6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-((1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)amino)nicotinamide(390);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-((1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)amino)-N-isobutylnicotinamide(391);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-((1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)amino)-N-(2-ethoxyethyl)nicotinamide(392);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-((1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)amino)-N-ethylnicotinamide(393);(R)-6-(5-chloro-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-((1-(difluoromethyl)-1H-pyrazol-4-yl)amino)-N-(2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide (394);(R)-6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(2,3-difluoro-3-methylbutyl)-4-((1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)amino)nicotinamide(395);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-((1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)amino)-N-((1R,4R)-4-(2-hydroxypropan-2-yl)cyclohexyl)nicotinamide(396);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(2,2-difluoro-3-hydroxy-3-methylbutyl)-4-((1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)amino)nicotinamide(397);(R)-6-(6-chloro-3H-imidazo[4,5-b]pyridin-3-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-((1-methyl-1H-pyrazol-4-yl)amino)nicotinamide(398);(R)-6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-((1-methyl-1H-pyrazol-4-yl)amino)nicotinamide (399);(R)-6-(6-chloro-3H-imidazo[4,5-b]pyridin-3-yl)-4-((1-(difluoromethyl)-1H-pyrazol-4-yl)amino)-N-(2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide (400);(R)-6-(6-cyano-3H-imidazo[4,5-b]pyridin-3-yl)-4-((1-(difluoromethyl)-1H-pyrazol-4-yl)amino)-N-(2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide (401);(R)-6-(6-chloro-3H-imidazo[4,5-b]pyridin-3-yl)-N-(2,3-difluoro-3-methylbutyl)-4-((1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)amino)nicotinamide(402);(R)-6-(6-cyano-3H-imidazo[4,5-b]pyridin-3-yl)-N-(2,3-difluoro-3-methylbutyl)-4-((1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)amino)nicotinamide(403);(R)-6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-((3-cyclopropyl-1H-pyrazol-5-yl)amino)-N-(2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide(404);(R)-6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-((3-methyl-1H-pyrazol-5-yl)amino)nicotinamide(405);(R)-6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-((3-isopropyl-1H-pyrazol-5-yl)amino)nicotinamide(406);(R)-6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-((1-(2,2-difluoroethyl)-1H-pyrazol-3-yl)amino)-N-(2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide(407);(R)-6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)amino)nicotinamide(408);(R)-6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-((1-methyl-1H-pyrazol-5-yl)amino)nicotinamide(409);(R)-6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-((1-(pyrimidin-2-yl)-1H-pyrazol-4-yl)amino)nicotinamide (410);(R)-6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-((1-(5-fluoropyrimidin-2-yl)-1H-pyrazol-4-yl)amino)nicotinamide (411);(R)-6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-((3-phenyl-1H-pyrazol-5-yl)amino)nicotinamide(412);(R)-6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-((1,3-dimethyl-1H-pyrazol-5-yl)amino)-N-(2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide(413);6-(5-cyano-1H-indol-1-yl)-N-((1R,4R)-4-(2-hydroxypropan-2-yl)cyclohexyl)-4-(isopropylamino)nicotinamide(414);6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-(4-hydroxybicyclo[2.2.1]heptan-1-yl)-4-(isopropylamino)nicotinamide(415);(R)-6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-((3-sulfamoylphenyl)amino)nicotinamide(416);N-(3-(tert-butoxy)propyl)-6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-4-(isopropylamino)nicotinamide (417);(R)-6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-((3-methoxyphenyl)amino)nicotinamide(418);(R,E)-6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-((3-hydroxy-3-methylbut-1-en-1-yl)amino)nicotinamide(419);6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-((1R,4R)-4-fluoro-4-((1-methyl-1H-imidazol-2-yl)cyclohexyl)-4-(isopropylamino)nicotinamide(420);(R)-4-(benzo[d]oxazol-6-ylamino)-6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide(421);6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4-((3-hydroxybutyl)amino)nicotinamide(422);(R)-6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-(((6-methylpyridin-3-yl)methyl)amino)nicotinamide (423);(R)-6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-((1-methyl-1H-pyrazol-5-yl)amino)nicotinamide(424);(R)-6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-((3,3,3-trifluoropropyl)amino)nicotinamide(425);6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4-((4-fluorobutan-2-yl)amino)nicotinamide (426);6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4-((4-fluorobutan-2-yl)amino)nicotinamide(427);4-(cyclopropylamino)-6-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-((1R,4R)-4-((2-hydroxypropan-2-yl)cyclohexyl)nicotinamide(428);6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-4-(cyclopropylamino)-N-((1R,4R)-4-(2-hydroxypropan-2-yl)cyclohexyl)nicotinamide (429);(R)-6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-4-((3-cyano-2-fluorophenyl)amino)-N-(2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide(430);(R)-4-((3-(1H-imidazol-2-yl)phenyl)amino)-6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide(431);6-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-1-yl)-4-(((S)-1-hydroxypropan-2-yl)amino)-N-((1R,4S)-4-(2-hydroxypropan-2-yl)cyclohexyl)nicotinamide(432);(R)-6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-4-((4-(1-ethyl-1H-tetrazol-5-yl)phenyl)amino)-N-(2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide (433);(R)-6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-(2-fluoro-3-methoxy-3-methylbutyl)-4-(isopropylamino)nicotinamide(434);6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-4-(((R)-2-fluoro-3-(isopropylamino)-3-oxopropyl)amino)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide(435);(R)-4-((1H-benzo[d][1,2,3]triazol-6-yl)amino)-6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide(436);(R)-6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-(oxetan-3-ylamino)nicotinamide(437);(R)-4-((1H-indazol-5-yl)amino)-6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide(438);(R)-4-((1H-benzo[d]imidazol-6-yl)amino)-6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide (439);6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4-(((R)-tetrahydrofuran-3-yl)amino)nicotinamide(440);6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4-(((S)-tetrahydrofuran-3-yl)amino)nicotinamide(441);(R)-6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-(2-fluoro-3-trideuteromethoxy-3-methylbutyl)-4-(isopropylamino)nicotinamide (442);6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N—((R)-2-fluoro-3-trideuteromethoxy-3-methylbutyl)-4-((3-(hydroxymethyl)cyclohexyl)amino)nicotinamide(443);6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-(4-(1-cyclopropyl-1-hydroxyethyl)cyclohexyl)-4-(isopropylamino)nicotinamide(444);6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4-((3-(hydroxymethyl)cyclohexyl)amino)nicotinamide(445);6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-(4-(1-cyclopropyl-1-hydroxyethyl)cyclohexyl)-4-(isopropylamino)nicotinamide(446);6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-4-(isopropylamino)-N-(1-(methylsulfonyl)piperidin-4-yl)nicotinamide (447);(R)-6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-(3-ethoxy-2-fluoro-3-methylbutyl)-4-(isopropylamino)nicotinamide(448);6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4-(((R)-1-(5-fluoropyrimidin-2-yl)pyrrolidin-3-yl)amino)nicotinamide(449);6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-4-(((R)-1-cyclopropylethyl)amino)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide(450);6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-4-(((S)-1-cyclopropylethyl)amino)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide(451);6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-4-(isopropylamino)-N-(2-(morpholine-4-sulfonamido)ethyl)nicotinamide(452);6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-4-(cyclopropylamino)-N-(2-(methylsulfonamido)ethyl)nicotinamide(453);6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4-((4-methylpentan-2-yl)amino)nicotinamide(454);6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4-(((3R,4S)-4-hydroxytetrahydrofuran-3-yl)amino)nicotinamide(455);6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4-(((3R,4S)-4-hydroxytetrahydrofuran-3-yl)amino)nicotinamide (456); (R)-tert-butyl3-((2-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-5-((2-fluoro-3-hydroxy-3-methylbutyl)carbamoyl)pyridin-4-yl)amino)azetidine-1-carboxylate(457);6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4-(((3R,4S)-4-fluorotetrahydrofuran-3-yl)amino)nicotinamide(458);6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4-(((3R,4S)-4-fluorotetrahydrofuran-3-yl)amino)nicotinamide(459);4-((2-(1H-imidazol-4-yl)cyclopropyl)amino)-6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide(460);6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4-((3-hydroxybutyl)amino)nicotinamide(461);6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4-((3-hydroxybutyl)amino)nicotinamide(462);(R)-6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-((1-(methylsulfonyl)piperidin-4-yl)amino)nicotinamide (463);(R)-6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-((1-phenylpiperidin-4-yl)amino)nicotinamide(464);6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4-(((R)-1-(methylsulfonyl)pyrrolidin-3-yl)amino)nicotinamide(465);6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4-((R)-pyrrolidin-3-ylamino)nicotinamide(466);6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-4-(isopropylamino)-N-(2-(4-methylpiperazin-1-yl)-2-oxoethyl)nicotinamide(467);(R)-4-((1-acetylazetidin-3-yl)amino)-6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide(468);4-(((R)-1-acetylpyrrolidin-3-yl)amino)-6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide (469);(R)-4-((1-acetylpiperidin-4-yl)amino)-6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide(470);(R)-4-((4-(1H-imidazol-1-yl)phenyl)amino)-6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide(471);(R)-6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-((1-(5-fluoropyrimidin-2-yl)azetidin-3-yl)amino)nicotinamide(472);6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4-(((R)-1-(3,3,3-trifluoropropanoyl)pyrrolidin-3-yl)amino)nicotinamide(473); (R)-methyl3-((2-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-5-(((R)-2-fluoro-3-hydroxy-3-methylbutyl)carbamoyl)pyridin-4-yl)amino)pyrrolidine-1-carboxylate(474);(R)-1-(4-((azetidin-3-ylmethyl)amino)-5-(2-fluoro-3-hydroxy-3-methylbutyl)carbamoyl)pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide(475);(R)-6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-((1-(methylsulfonyl)azetidin-3-yl)amino)nicotinamide(476);6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-4-(((R)-1-(2-cyanoacetyl)pyrrolidin-3-yl)amino)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide(477);(S)-6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-4-((1-hydroxypropan-2-yl)amino)-N-(2-(methylsulfonamido)ethyl)nicotinamide(478);6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-(2-(methylsulfonamido)ethyl)-4-((tetrahydro-2H-pyran-4-yl)amino)nicotinamide(479);(R)-6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-((2-morpholinoethyl)amino)nicotinamide(480); (R)-methyl3-((2-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-5-((2-fluoro-3-hydroxy-3-methylbutyl)carbamoyl)pyridin-4-yl)amino)azetidine-1-carboxylate(481);(R)-6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)nicotinamide(482);6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4-((2-(3-methylmorpholino)ethyl)amino)nicotinamide(483);6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-4-(4,4-difluorotetrahydrofuran-3-yl)amino)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide(484);6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-4-(4,4-difluorotetrahydrofuran-3-yl)amino)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide(485);4-(((1R,4R)-4-carbamoylcyclohexyl)amino)-6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide (486);6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-(2-(1-hydroxycyclopentyl)ethyl)-4-(isopropylamino)nicotinamide(487);6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4-((3-((2,2,2-trifluoroethyl)amino)cyclopentyl)amino)nicotinamide(488);6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4-((3-((2,2,2-trifluoroethyl)amino)cyclopentyl)amino)nicotinamide(489);4-((3-aminocyclopentyl)amino)-6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide(490);4-((3-aminocyclopentyl)amino)-6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide(491);4-((3-aminocyclopentyl)amino)-6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide(492);4-((3-aminocyclopentyl)amino)-6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide(493);6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-(2-fluoro-2-(3-hydroxyoxetan-3-yl)ethyl)-4-(isopropylamino)nicotinamide(494);6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-(2-fluoro-2-(3-hydroxyoxetan-3-yl)ethyl)-4-(isopropylamino)nicotinamide(495);6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4-(((2S)-3-hydroxy-5-methylhexan-2-yl)amino)nicotinamide (496);6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-((1S,3S)-3-(2-hydroxypropan-2-yl)cyclopentyl)-4-(isopropylamino)nicotinamide(497);(R)-isobutyl((1-(5-((2-fluoro-3-hydroxy-3-methylbutyl)carbamoyl)-4-(isopropylamino)pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)carbamate(498);(R)—N-(2-fluoro-3-hydroxy-3-methylbutyl)-6-(5-(3-hydroxy-3-methylbutanamido)methyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)-4-(isopropylamino)nicotinamide(499);(R)-6-(5-((3,3-diethylureido)methyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-(isopropylamino)nicotinamide (500);(R)-ethyl((1-(5-((2-fluoro-3-hydroxy-3-methylbutyl)carbamoyl)-4-(isopropylamino)pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)carbamate(501);(R)-isopropyl((1-(5-((2-fluoro-3-hydroxy-3-methylbutyl)carbamoyl)-4-(isopropylamino)pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)carbamate (502);(R)—N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-(isopropylamino)-6-(5-((3-methylbutanamido)methyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)nicotinamide(503);(R)-6-(5-((2-cyclopentylacetamido)methyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-(isopropylamino)nicotinamide(504);(R)-6-(5-(cyclopropanecarboxamidomethyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-(isopropylamino)nicotinamide (505);6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4-(((R)-2-fluoropropyl)amino)nicotinamide(506);6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4-(((S)-2-fluoropropyl)amino)nicotinamide(507);(R)-propyl((1-(5-((2-fluoro-3-hydroxy-3-methylbutyl)carbamoyl)-4-(isopropylamino)pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)carbamate(508);6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4-(((1R,3R)-3-(2-hydroxypropan-2-yl)cyclobutyl)amino)nicotinamide (509);(R)-6-(5-(butyramidomethyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-(isopropylamino)nicotinamide(510);(R)-6-(5-((2-cyclohexylacetamido)methyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-(isopropylamino)nicotinamide(511);(R)—N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-(isopropylamino)-6-(5-((4-methylpentanamido)methyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)nicotinamide(512);(R)—N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-(isopropylamino)-6-(5-((3-propylureido)methyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)nicotinamide(513);(R)-6-(5-((3-benzylureido)methyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-(isopropylamino)nicotinamide(514);(R)—N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-(isopropylamino)-6-(5-((2-phenylacetamido)methyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)nicotinamide(515);(R)-6-(5-((3-butylureido)methyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-(isopropylamino)nicotinamide(516);(R)-6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-(2,3-difluoro-3-methylbutyl)-4-((3-hydroxyphenyl)amino)nicotinamide(517);(R)—N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-(isopropylamino)-6-(5-((2-(tetrahydro-2H-pyran-4-yl)acetamido)methyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)nicotinamide(518);(R)-6-(5-((3,3-dimethylbutanamido)methyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-(isopropylamino)nicotinamide(519);N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4-(isopropylamino)-6-(5-((tetrahydrofuran-3-carboxamido)methyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)nicotinamide(520);(R)-6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-((5-(2-hydroxypropan-2-yl)thiazol-2-yl)amino)nicotinamide(521);(R)-6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-((3-cyanophenyl)amino)-N-(2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide(522);(R)-6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-((4-cyanophenyl)amino)-N-(2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide(523);(R)-4-(benzo[d]thiazol-6-ylamino)-6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide(524);(R)-1-(4-(benzo[d]oxazol-6-ylamino)-5-(2-fluoro-3-hydroxy-3-methylbutyl)carbamoyl)pyridin-2-yl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide(525);(R)-4-((4-(1H-1,2,4-triazol-1-yl)phenyl)amino)-6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide(526);(R)-6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-((4-(1-methyl-1H-tetrazol-5-yl)phenyl)amino)nicotinamide(527);(R)-6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-((3-cyano-2-fluorophenyl)amino)-N-(2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide(528);(R)-6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(2,3-difluoro-3-methylbutyl)-4-((4-(1-methyl-1H-tetrazol-5-yl)phenyl)amino)nicotinamide (529);(R)-6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-(5-methyl-1,3,4-thiadiazol-2-yl)amino)nicotinamide(530);(R)-6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-((4-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)nicotinamide(531);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4-(((R)-1-(5-fluoropyrimidin-2-yl)pyrrolidin-3-yl)amino)nicotinamide(532);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4-(((S)-1-(5-fluoropyrimidin-2-yl)pyrrolidin-3-yl)amino)nicotinamide(533);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4-(((R)-1-(5-fluoropyrimidin-2-yl)pyrrolidin-3-yl)amino)nicotinamide(534);(R)-6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-((1-phenylpiperidin-4-yl)amino)nicotinamide(535);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4-(((R)-1-(5-methoxypyrimidin-2-yl)pyrrolidin-3-yl)amino)nicotinamide(536);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4-(((R)-1-(pyrimidin-2-yl)pyrrolidin-3-yl)amino)nicotinamide(537);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-(((R)-1-(2,4-difluorobenzoyl)pyrrolidin-3-yl)amino)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide (538);(R)-6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-((1-(5-fluoropyrimidin-2-yl)azetidin-3-yl)amino)nicotinamide(539);(R)-6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-((1-(5-fluoropyrimidin-2-yl)piperidin-4-yl)amino)nicotinamide(540);(R)-4-((1-(5-chloropyrimidin-2-yl)azetidin-3-yl)amino)-6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide(541); (R)-methyl3-((2-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-5-((2-fluoro-3-hydroxy-3-methylbutyl)carbamoyl)pyridin-4-yl)amino)azetidine-1-carboxylate (542); (R)-ethyl3-((2-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-5-((2-fluoro-3-hydroxy-3-methylbutyl)carbamoyl)pyridin-4-yl)amino)azetidine-1-carboxylate (543);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4-(((R)-tetrahydrofuran-3-yl)amino)nicotinamide,TFA salt (544);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4-(((S)-tetrahydrofuran-3-yl)amino)nicotinamide, TFA salt (545);(R)-6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-(oxetan-3-ylamino)nicotinamide(546);6-(5-fluoro-1H-pyrazolo[3,4-b]pyridin-1-yl)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4-((tetrahydro-2H-pyran-3-yl)amino)nicotinamide(547);6-(6-cyano-3H-imidazo[4,5-b]pyridin-3-yl)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4-(((R)-tetrahydrofuran-3-yl)amino)nicotinamide(548);(R)-6-(5-cyano-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-(oxetan-3-ylamino)nicotinamide(549);(R)-6-(5-fluoro-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-(oxetan-3-ylamino)nicotinamide(550);(R)-6-(5-chloro-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-(oxetan-3-ylamino)nicotinamide(551);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-((1R,4R)-4-methoxycyclohexyl)-4-(oxetan-3-ylamino)nicotinamide(552);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(3-hydroxy-3-methylbutyl)-4-(oxetan-3-ylamino)nicotinamide(553);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-(4,4-difluorotetrahydrofuran-3-yl)amino)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide(554);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-((1R,4R)-4-(2-hydroxypropan-2-yl)cyclohexyl)-4-(oxetan-3-ylamino)nicotinamide(555);6-(5-chloro-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-((1R,4R)-4-(2-hydroxypropan-2-yl)cyclohexyl)-4-(oxetan-3-ylamino)nicotinamide(556);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-isopentyl-4-(oxetan-3-ylamino)nicotinamide(557);6-(6-amino-5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(2-cyclopropylethyl)-4-(oxetan-3-ylamino)nicotinamide (558);6-(6-amino-5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-butyl-4-(oxetan-3-ylamino)nicotinamide(559);6-(6-amino-5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-isopentyl-4-(oxetan-3-ylamino)nicotinamide(560);N-butyl-6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-(oxetan-3-ylamino)nicotinamide(561);(R)-6-(5-fluoro-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-((tetrahydro-2H-pyran-4-yl)amino)nicotinamide(562);(R)-6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-((3,3,3-trifluoropropyl)amino)nicotinamide(563);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-(isopropylamino)-N-(5-methoxypyrazin-2-yl)nicotinamide(564);N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4-((2-morpholinopropyl)amino)-6-(7H-pyrrolo[2,3-d]pyrimidin-7-yl)nicotinamide(565);N-((2H-tetrazol-5-yl)methyl)-6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-(isopropylamino)nicotinamide(566);(R)-6-(5-cyano-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-(isopropylamino)nicotinamide(567);(R)-6-(6-cyano-3H-imidazo[4,5-b]pyridin-3-yl)-4-(ethylamino)-N-(2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide(568);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4-(((S)-1-hydroxy-3-methylbutan-2-yl)amino)nicotinamide (569);(R)-6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-((2-methyl-2-morpholinopropyl)amino)nicotinamide(570);(R)-6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-((oxazol-4-ylmethyl)amino)nicotinamide(571);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4-(((R)-3-hydroxybutyl)amino)nicotinamide (572);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4-(((R)-3-hydroxybutyl)amino)nicotinamide(573);(R)-6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-((2,2-difluoroethyl)amino)-N-(2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide(574);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-((2-fluoro-3-hydroxy-2-methylpropyl)amino)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide(575);(R)-6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-(neopentylamino)nicotinamide(576);(R)-6-(6-amino-5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-(ethylamino)-N-(2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide(577);(R)-6-(6-amino-5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-(propylamino)nicotinamide(578);(R)-6-(6-amino-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-(isopropylamino)nicotinamide(579);(R)-6-(6-amino-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-4-(ethylamino)-N-(2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide(580);(R)-6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-(((1-fluorocyclobutyl)methyl)amino)nicotinamide(581);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4-(((R)-2-fluoropropyl)amino)nicotinamide (582);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4-(((S)-2-fluoropropyl)amino)nicotinamide(583);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-(isopropylamino)-N-(1-(1-(methylsulfonyl)azetidine-3-carbonyl)piperidin-4-yl)nicotinamide(584);(R)-4-((3-amino-2,2-dimethylpropyl)amino)-6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide(585);(R)-6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-((2-(methylsulfonamido)ethyl)amino)nicotinamide(586);(R)-1,1,1-trifluoro-2-methylpropan-2-yl(2-((2-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-5-(2-fluoro-3-hydroxy-3-methylbutyl)carbamoyl)pyridin-4-yl)amino)ethyl)carbamate (587);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4-(((S)-1-hydroxybutan-2-yl)amino)nicotinamide(588);6-(5-chloro-1H-pyrazolo[3,4-b]pyridin-1-yl)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4-(((S)-1-hydroxybutan-2-yl)amino)nicotinamide(589);6-(6-amino-5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4-(((S)-2-fluoropropyl)amino)nicotinamide(590);6-(6-amino-5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4-(((R)-2-fluoropropyl)amino)nicotinamide(591);(R)-6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-(propylamino)nicotinamide(592);(R)-6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-((2-methoxy-2-methylpropyl)amino)nicotinamide(593);6-(5-chloro-1H-pyrazolo[3,4-b]pyridin-1-yl)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4-((2-hydroxy-3-methylbutyl)amino)nicotinamide(594);(R)-6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-((3-fluoropropyl)amino)nicotinamide(595);6-(5-chloro-1H-pyrazolo[3,4-b]pyridin-1-yl)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4-((2-hydroxy-3-methylbutyl)amino)nicotinamide (596);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4-((2-hydroxy-3-methylbutyl)amino)nicotinamide(597);(R)-6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-((2-(difluoromethoxy)ethyl)amino)-N-(2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide(598);(R)-6-(6-amino-5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-((3-fluoro-3-methylbutyl)amino)nicotinamide(599);(R)-6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-((3-fluoro-3-methylbutyl)amino)nicotinamide(600);(R)-6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-((2-(difluoromethoxy)-2-methylpropyl)amino)-N-(2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide(601);6-(5-chloro-1H-pyrazolo[3,4-b]pyridin-1-yl)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4-(((R)-2-fluorobutyl)amino)nicotinamide(602);(R)-6-(5-chloro-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-((2-(difluoromethoxy)-2-methylpropyl)amino)-N-(2-fluro-3-hydroxy-3-methylbutyl)nicotinamide(603);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4-((3-fluorobutyl)amino)nicotinamide(604);(R)-6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-((cyclopropylmethyl)amino)-N-(2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide(605);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4-(((1R,4R)-4-(2-hydroxypropan-2-yl)cyclohexyl)amino)nicotinamide(606);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4-(((1s,4S)-4-hydroxy-4-methylcyclohexyl)amino)nicotinamide(607);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4-(((1R,4R)-4-hydroxy-4-methylcyclohexyl)amino)nicotinamide (608);6-(5-fluoro-1H-pyrazolo[3,4-b]pyridin-1-yl)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4-((3-hydroxycyclopentyl)amino)nicotinamide(609);6-(5-fluoro-1H-pyrazolo[3,4-b]pyridin-1-yl)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4-((3-hydroxycyclopentyl)amino)nicotinamide(610);6-(5-fluoro-1H-pyrazolo[3,4-b]pyridin-1-yl)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4-((3-hydroxycyclopentyl)amino)nicotinamide (611);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4-(((1R,3S)-3-(2-hydroxypropan-2-yl)cyclohexyl)amino)nicotinamide (612);(R)-6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-((4-hydroxybicyclo[2.2.1]heptan-1-yl)amino)nicotinamide(613);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-((3,3-difluorocyclopentyl)amino)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide(614);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-((3,3-difluorocyclopentyl)amino)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide(615);(R)-6-(5-cyano-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl)-4-(cyclopropylamino)-N-(2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide(616);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4-(((1S,3S)-3-(2-hydroxypropan-2-yl)cyclopentyl)amino)nicotinamide(617);6-(5-fluoro-1H-pyrazolo[3,4-b]pyridin-1-yl)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4-((3-fluorocyclopentyl)amino)nicotinamide(618);6-(5-fluoro-1H-pyrazolo[3,4-b]pyridin-1-yl)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4-((3-fluorocyclopentyl)amino)nicotinamide (619);6-(5-fluoro-1H-pyrazolo[3,4-b]pyridin-1-yl)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4-((3-fluorocyclopentyl)amino)nicotinamide(620);6-(5-fluoro-1H-pyrazolo[3,4-b]pyridin-1-yl)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4-((3-fluorocyclopentyl)amino)nicotinamide(621);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4-(((1R,4R)-4-(oxetan-3-ylamino)cyclohexyl)amino)nicotinamide(622);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-(((1R,4R)-4-(cyclopropanecarboxamido)cyclohexyl)amino)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide(623);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4-(((1R,5S)-3-hydroxyadamantan-1-yl)amino)nicotinamide (624);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4-((3-fluorocyclopentyl)amino)nicotinamide(625);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4-((3-fluorocyclopentyl)amino)nicotinamide(626);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4-((3-fluorocyclopentyl)amino)nicotinamide (627);6-(5-chloro-1H-pyrazolo[3,4-b]pyridin-1-yl)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4-(((1S,3S)-3-(2-hydroxypropan-2-yl)cyclopentyl)amino)nicotinamide (628);6-(6-amino-5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-(((1R,2R)-2-fluorocyclohexyl)amino)-N-((1R,4R)-4-(methylcarbamoyl)cyclohexyl)nicotinamide(629);6-(6-amino-5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-(((1S,2S)-2-fluorocyclohexyl)amino)-N-((1R,4S)-4-(methylcarbamoyl)cyclohexyl)nicotinamide(630);(R)-6-(6-amino-5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-(cyclopropylamino)-N-(2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide(631);6-(6-amino-5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4-(((1R,5S)-3-hydroxyadamantan-1-yl)amino)nicotinamide(632);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-(((1R,4R)-4-(2,2-difluoroacetamido)cyclohexyl)amino)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide(633);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4-(((1R,4R)-4-((2-fluorobenzamido)cyclohexyl)amino)nicotinamide(634);(R)-4-(bicyclo[1.1.1]pentan-2-ylamino)-6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide (635);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N—((R)-2,3-difluoro-3-methylbutyl)-4-(((1R,5S)-3-hydroxyadamantan-1-yl)amino)nicotinamide(636);(R)-6-(6-amino-5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-(bicyclo[1.1.1]pentan-1-ylamino)-N-(2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide(637);4-((3-aminocyclopentyl)amino)-6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide (638);4-((3-aminocyclopentyl)amino)-6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide(639);4-((3-aminocyclopentyl)amino)-6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide(640);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4-(((1R,4R)-4-(isopropylcarbamoyl)cyclohexyl)amino)nicotinamide(641);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4-(((1R,2R)-2-(hydroxymethyl)cyclopropyl)amino)nicotinamide(642);6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4-(((1R,2R)-2-(hydroxymethyl)cyclopropyl)amino)nicotinamide (643);(R)-6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-((3,3-difluorocyclobutyl)amino)-N-(2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide(644);6-(5-chloro-1H-pyrazolo[3,4-b]pyridin-1-yl)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4-(((1R,2R)-2-(hydroxymethyl)cyclopropyl)amino)nicotinamide(645); and6-(5-chloro-1H-pyrazolo[3,4-b]pyridin-1-yl)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4-(((1R,2R)-2-(hydroxymethyl)cyclopropyl)amino)nicotinamide(646).

In any aspect or embodiment described herein, the PTM is represented byFormula PTM-Va (which related to Formula I from InternationalPublication No. 2013/042137 A1 and Formula I from InternationalPublication No. 2015/104688 A1, which are incorporated herein in theirentirety for all purposes) or PTM-Vb:

wherein:

-   -   X₁ and X₃ of PTM-Va or PTM-Vb independently are CH or N; X₂ of        PTM-V is CR₂ or N; provided one and not more than one of X₁, X₂        or X₃ is N;    -   Y of PTM-Va or PTM-Vb is —CH₂— or O;    -   Ring Z of PTM-Va or PTM-Vb is aryl, heteroaryl, or heterocyclyl;    -   A of PTM-Va or PTM-Vb is O, S, or NH;    -   R₁ of PTM-Va or PTM-Vb at each occurrence, is independently        hydrogen, cyano, halo, hydroxy, —NO₂, —NR₅R₆, optionally        substituted alkyl, optionally substituted aryl, optionally        substituted cycloalkyl, optionally substituted heterocycloalkyl,        optionally substituted heterocyclyl or optionally substituted        heteroaryl, wherein the substituent, in each occurrence, is        independently selected from alkyl, alkoxy, haloalkyl, cyano,        aminoalkyl, halo, hydroxyl, hydroxyalkyl, —NR⁷R⁸, or COOR⁹;    -   R₂ of PTM-Va or PTM-Vb is hydrogen, optionally substituted        cycloalkyl, optionally substituted aryl, optionally substituted        heterocyclyl or —NR_(a)R_(b); wherein the substituent is alkyl,        amino, halo or hydroxyl;    -   R₃ of PTM-Va or PTM-Vb at each occurrence is independently        selected from hydrogen, carboxy, cyano, hydroxy, hydroxyalkyl,        alkyl, aryl, heteroaryl, —SO₂R⁷, hydroxyl or oxo;    -   R₄ of PTM-Va or PTM-Vb at each occurrence is independently        selected from hydrogen, halogen, alkyl, aryl, heterocycloalkyi,        heterocycloalkylalkyl, heteroaryl, Y-arylalkyl or —Y-cycloalkyl;        wherein cycloalkyl, aryl, heterocycloalkyi,        heterocycloalkylalkyl, heteroaryl and arylalkyl can be        optionally substituted with hydroxy, alkyl, haloalkyl, cyano or        halo;    -   Y₁ of PTM-Va or PTM-Vb is selected from direct bond, O, —C(O)—        or NR⁹;    -   R₅ and R₆ of PTM-Va or PTM-Vb are independently selected from        hydrogen, hydroxyalkyl, aminoalkyl, acyl, optionally substituted        alkyl, optionally substituted heterocyclyl, optionally        substituted aryl; wherein the optional substituent, in each        occurrence, is independently selected from halo, haloalkyl or        —COOR₉;    -   R₇ and R₈ of PTM-Va or PTM-Vb are independently hydrogen, alkyl,        acyl, heterocyclyl, —COR₉ or —COOR₉;    -   R₉ of PTM-Va or PTM-Vb at each occurence is independently        selected from hydrogen or alkyl;    -   R_(9a) of PTM-Vb is selected from hydrogen, halo, optionally        substituted alkoxy (e.g., optionally substituted C₁-C₄ alkoxy),        optionally substituted alkyl (e.g., C₁-C₄ alkyl optionally        substituted with halo or hydroxy), hydroxyalkyl (e.g. C₁-C₄        hydroxyalkyl), or haloalkyl (e.g., C₁-C₄ haloalkyl);    -   “m”, “n” and “q” of PTM-Va or PTM-Vb are independently selected        from 0, 1, 2, or 3;    -   “p” of PTM-Va or PTM-Vb is 0 or 1; and    -   the PTM-Va or PTM-Vb is covalently joined to a ULM, a chemical        linker group (L), a CLM, an ILM, a VLM, MLM, a ULM′, a CLM′, a        ILM′, a VLM′, a MLM′, or combination thereof.

In any aspect or embodiment described herein, the PTM-V is covalentlyjoined to a ULM, a chemical linker group (L), a CLM, an ILM, a VLM, MLM,a ULM′, a CLM′, a ILM′, a VLM′, a MLM′, or combination thereof via an Rgroup (e.g., R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, 9⁹, 9^(a), R^(a), orR_(b)).

In any aspect or embodiment described herein, the PTM of PTM-Va orPTM-Vb may comprise at least one of:

-   -   X₁, X₂ and X₃ of PTM-Va or PTM-Vb are CH;    -   Y of PTM-Va or PTM-Vb is O;    -   Ring Z of PTM-Va or PTM-Vb is aryl or heteroaryl;    -   A of PTM-Va or PTM-Vb is O, S, or NH;    -   R₁ of PTM-Va or PTM-Vb, at each occurrence, is independently        hydrogen, cyano, halo, hydroxy, —NO₂, —NR₅R₆, optionally        substituted alkyl, optionally substituted aryl, optionally        substituted cycloalkyl, optionally substituted heterocycloalkyl,        or optionally substituted heteroaryl, wherein the substituent,        in each occurrence, is independently selected from is alkyl,        haloalkyl, halo, cyano, —NR₇R₈, or COOR₉;    -   R₃ of PTM-Va or PTM-Vb, at each occurrence, is independently        selected from hydrogen, carboxy, cyano, hydroxy, hydroxyalkyl,        alkyl, aryl, heteroaryl, —SO₂R₇ or OXO;    -   R₄ of PTM-Va or PTM-Vb at each occurence is independently        selected from hydrogen, halogen, alkyl, aryl, heterocycloalkyi,        heterocycloalkylalkyl, heteroaryl, Y₁-arylalkyl or        —Y₁-cycloalkyl; wherein cycloalkyl, aryl, heterocycloalkyi,        heterocycloalkylalkyl, heteroaryl and arylalkyl can be        optionally substituted with hydroxy, alkyl, haloalkyl, cyano or        halo;    -   Y₁ of PTM-Va or PTM-Vb is selected from direct bond, O, —C(O)—        or NR⁹;    -   R₅ and R₆ of PTM-Va or PTM-Vb are independently selected from        hydrogen, hydroxyalkyl, aminoalkyl, acyl, optionally substituted        alkyl, optionally substituted heterocyclyl, optionally        substituted aryl; wherein the optional substituent, in each        occurrence, is independently selected from halo, haloalkyl or        —COOR⁹;    -   R₇ and R₈ of PTM-Va or PTM-Vb are independently hydrogen, alkyl,        acyl, heterocyclyl, —COR⁹ or —COOR⁹;    -   R₉ of PTM-Va or PTM-Vb at each occurence is independently        selected from hydrogen or alkyl;    -   “m”, “n” and “q” of PTM-Va or PTM-Vb are independently selected        from 0, 1, 2, or 3; and    -   “p” of PTM-Va or PTM-Vb is 0 or 1.

In any aspect or embodiment described herein, Ring Z of PTM-Va or PTM-Vbis pyridine or phenyl.

In any aspect or embodiment described herein, R₁ of PTM-Va or PTM-Vb isoptionally substituted heteroaryl (for example pyrazole, pyridine,pyrimidine, quinoline, indazole or 7-azaindole).

In any aspect or embodiment described herein, R₄ of PTM-Va or PTM-Vb ishydrogen, alkyl (for example C₁₋₄ alkyl), heterocycloalkyl (for examplepiperidine, pyrrolidine or morpholine), heterocycloalkylalkyl (forexample pyrrolidin-1-ylmethyl), Y₁-cycloalkyl (for example Y₁ is a bond,NH or NCH₃ and cycloalkyl is cyclopropyl), aryl (for example phenyl) orheteroaryl (for example pyridine).

In any aspect or embodiment described herein, the PTM of PTM-V isselected from(PTM-V_(A)-1)N-(2-morpholino-5-(piperidin-1-yl)benzo[d]oxazol-6-yl)-6-(1H-pyrazol-5-yl)picolinamide;(PTM-V_(A)-2)N-(2-morpholino-5-phenylbenzo[d]oxazol-6-yl)-6-(1H-pyrrolo[2,3-b]pyridin-5-yl)picolinamide;(PTM-VA-3)6′-amino-N-(2-morpholino-5-phenylbenzo[d]oxazol-6-yl)-[2,3′-bipyridine]-6-carboxamide;(PTM-VA-4)N-(2-morpholino-5-(piperidin-1-yl)benzo[d]oxazol-6-yl)-6-(1H-pyrazol-4-yl)picolinamide;(PTM-VA-5)N-(2-morpholino-5-(pyrrolidin-1-yl)benzo[d]oxazol-6-yl)-6-(1H-pyrrolo[2,3-b]pyridin-5-yl)picolinamide;(PTM-VA-6)6′-amino-N-(5-(cyclopropylamino)-2-morpholinobenzo[d]oxazol-6-yl)-[2,3′-bipyridine]-6-carboxamide;(PTM-VA-7)6′-amino-N-(5-(4-hydroxypiperidin-1-yl)-2-morpholinobenzo[d]oxazol-6-yl)-[2,3′-bipyridine]-6-carboxamide;(PTM-VA-8)6′-amino-N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinobenzo[d]oxazol-6-yl)-[2,3′-bipyridine]-6-carboxamide;(PTM-VA-9)6′-amino-N-(5-(benzyloxy)-2-morpholinobenzo[d]oxazol-6-yl)-[2,3′-bipyridine]-6-carboxamide;(PTM-VA-10)N-(5-(4-hydroxypiperidin-1-yl)-2-morpholinobenzo[d]oxazol-6-yl)-6-(1H-pyrazol-5-yl)picolinamide;(PTM-VA-11)N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinobenzo[d]oxazol-6-yl)-6-(1H-pyrazol-5-yl)picolinamide;(PTM-VA-12)N-(5-(benzyloxy)-2-morpholinobenzo[d]oxazol-6-yl)-6-(1H-pyrazol-5-yl)picolinamide;(PTM-VA-13)6′-amino-N-(2-morpholino-5-(piperidin-1-yl)benzo[d]thiazol-6-yl)-[2,3′-bipyridine]-6-carboxamide;(PTM-VA-14)N-(2-morpholino-5-(piperidin-1-yl)benzo[d]thiazol-6-yl)-6-(1H-pyrazol-5-yl)picolinamide;(PTM-VA-15)6′-amino-N-(2-morpholino-5-(piperidin-1-yl)benzo[d]oxazol-6-yl)-[2,3′-bipyridine]-6-carboxamide;(PTM-VA-16)6′-amino-N-(5-(2-hydroxyphenyl)-2-morpholinobenzo[d]oxazol-6-yl)-[2,3′-bipyridine]-6-carboxamide;(PTM-V_(A)-17)N-(5-cyclopropyl-2-morpholinobenzo[d]oxazol-6-yl)-6-(1H-pyrazol-5-yl)picolinamide;(PTM-V_(A)-18)5-bromo-N-(2-morpholino-5-(piperidin-1-yl)benzo[d]oxazol-6-yl)-1H-pyrrolo[2,3-b]pyridine-1-carboxamide;(PTM-V_(A)-19)N-(2-morpholino-5-(piperidin-1-yl)benzo[d]oxazol-6-yl)-6-(1H-pyrrolo[2,3-b]pyridin-5-yl)picolinamide;(PTM-V_(A)-2O)N-(7-methyl-2-morpholinobenzo[d]oxazol-6-yl)-6-(1H-pyrrolo[2,3-b]pyridin-5-yl)picolinamide;(PTM-V_(A)-21)N-(7-methyl-2-morpholinobenzo[d]oxazol-6-yl)-[2,4′-bipyridine]-6-carboxamide;(PTM-V_(A)-22)N-(7-isobutyl-2-morpholinobenzo[d]oxazol-6-yl)-[2,4′-bipyridine]-6-carboxamide;(PTM-V_(A)-23)N-(7-isobutyl-2-morpholinobenzo[d]oxazol-6-yl)-6-(1H-pyrrolo[2,3-b]pyridin-5-yl)picolinamide;(PTM-V_(A)-24)N-(2-morpholino-4-phenylbenzo[d]oxazol-6-yl)-6-(1H-pyrrolo[2,3-b]pyridin-5-yl)picolinamide;(PTM-V_(A)-25)6′-amino-N-(2-morpholino-4-phenylbenzo[d]oxazol-6-yl)-[2,3′-bipyridine]-6-carboxamide;(PTM-V_(A)-26)N-(2-morpholino-4-(pyridin-4-yl)benzo[d]oxazol-6-yl)-[2,4′-bipyridine]-6-carboxamide;(PTM-V_(A)-27)6′-amino-N-(2-morpholino-4-(pyridin-4-yl)benzo[d]oxazol-6-yl)-[2,3′-bipyridine]-6-carboxamide;(PTM-V_(A)-28)N-(2,-dimorpholinobenzo[d]thiazol-6-yl)-6-(1H-pyrrolo[2,3-b]pyridin-5-yl)picolinamide;(PTM-V_(A)-29)6′-amino-N-(5-cyclopropyl-2-morpholinobenzo[d]thiazol-6-yl)-[2,3′-bipyridine]-6-carboxamide;(PTM-V_(A)-30)N-(5-cyclopropyl-2-morpholinobenzo[d]thiazol-6-yl)-6-(1H-pyrazol-5-yl)picolinamide;(PTM-V_(A)-31)N-(5-(cyclopropyl(methyl)amino)-2-morpholinobenzo[d]thiazol-6-yl)-6-(1H-pyrazol-5-yl)picolinamide:(PTM-V_(A)-32)6′-amino-N-(5-isobutyl-2-morpholinobenzo[d]thiazol-6-yl)-[2,3′-bipyridine]-6-carboxamide;(PTM-V_(A)-33) 6′-amino-N-(2-morpholino-5-(pyrrolidin-1-ylmethyl)benzo[d]thiazol-6-yl)-[2,3′-bipyridine]-6-carboxamide; (PTM-V_(A)-34)tert-butyl (1-(6-((2-morpholinobenzo[d]oxazol-6-yl)carbamoyl)pyridin-2-yl)pyrrolidin-3-yl)carbamate; (PTM-V_(A)-35)6-(3-aminopyrrolidin-1-yl)-N-(2-morpholinobenzo[d]oxazol-6-yl)picolinamide;(PTM-V_(A)-36)2′-fluoro-N-(2-morpholinobenzo[d]oxazol-6-yl)-[2,4-bipyridine]-6-carboxamide;(PTM-V_(A)-37)N-2morpholinobenzo[d]oxazol-6-yl)-[2,3′-bipyridine]-6-carboxamide:(PTM-V_(A)-38)N-2morpholinobenzo[d]oxazol-6-yl)-6-(pyrimidin-5-yl)picolinamide;(PTM-V_(A)-39)N-2morpholinobenzo[d]oxazol-6-yl)-[2,4′-bipyridine]-6-carboxamide;(PTM-V_(A)-40) 6-2aminopyrimidin-5-yl)-N-(2-morpholinobenzo[d]oxazol-6-yl)picolinamide;(PTM-V_(A)-41)6′-amino-N-(2-morpholinobenzo[d]oxazol-6-yl)-[2,3′-bipyridine]-6-carboxamide;(PTM-V_(A)-42)6′-acetamido-N-(2-morpholinobenzo[d]oxazol-6-yl)-[2,3′-bipyridine]-6-carboxamide;(PTM-V_(A)-43)6-(1H-indazol-5-yl)-N-(2-morpholinobenzo[d]oxazol-6-yl)picolinamide;(PTM-V_(A)-44)N-(2-morpholinobenzo[d]oxazol-6-yl)-6-(quinolin-6-yl)picolinamide;(PTM-V_(A)-45)N-(2-morpholinobenzo[d]oxazol-6-yl)-6-(1H-pyrrolo[2,3-b]pyridin-5-ypicolinamide: (PTM-V_(A)-46)N-(2-morpholinobenzo[d]oxazol-6-yl)-6-(H-pyrazol-5-yl)picolinamide;(PTM-VA-47)N-(5-chloro-2-morpholinobenzo[d]oxazol-6-yl)-6-(1H-pyrrolo[2,3-b]pyridin-5-yl)picolinamide;(PTM-V_(A)-48)6′-amino-N-(2-morpholino-1H-benzo[d]imidazol-6-yl)-[2,3′-bipyridine]-6-carboxamide;(PTM-V_(A)-49)6′-amino-N-(2-morpholinobenzo[d]thiazol-6-yl)-[2,3′-bipyridine]-6-carboxamide;(PTM-V_(A)-50) tert-butyl4-((6-((2-morpholinobenzo[d]oxazol-6-yl)carbamoyl)pyridin-2-yl)amino)piperidine-1-carboxylate; (PTM-V_(A)-51) tert-butyl3-((6-((2-morpholinobenzo[d]oxazol-6-yl)carbamoyl)pyridin-2-yl)amino)pyrrolidine-1-carboxylate;(PTM-V_(A)-52)N-(2-morpholinobenzo[d]oxazol-6-yl)-6-((3-(trifluoromethyl)phenyl)amino)picolinamide:(PTM-V_(A)-53)6-((2-aminoethyl)amino)-N-(2-moφholinobenzo[d]oxazol-6-yl)picolinamide;(PTM-V_(A)-54)6-((2-hydroxyethyl)amino)-N-(2-moφholinobenzo[d]oxazol-6-yl)picolinamide;(PTM-V_(A)-55)6-((2-aminoethyl)amino)-N-(2-rrlOφholinobenzo[d]thiazol-6-yl)picolinamide;(PTM-V_(A)-56)6-((2-hydroxyethyl)amino)-N-(2-moφholinobenzo[d]thiazol-6-yl)picolinamide;(PTM-V_(A)-57)N-(2-moφholinobenzo[d]oxazol-6-yl)-3-nitrobenzamide; and(PTM-V_(A)-58)N-(2-(2,6-dimethylrnoholino)benzo[d]oxazol-6-yl)-[2,4′-bipyridine]-6-carboxamide.

In any aspect or embodiment described herein, the PTM of PTM-Va orPTM-Vb may comprise at least one of:

-   -   X₁ and X₃ of PTM-Va or PTM-Vb independently are CH or N; X₂ of        PTM-V is CR₂ or N; provided one and not more than one of X₁, X₂        or X₃ is N;    -   Y of PTM-Va or PTM-Vb is —CH₂— or O;    -   Ring Z of PTM-Va or PTM-Vb is aryl or heterocyclyl;    -   A of PTM-Va or PTM-Vb is O or S;    -   R₁ of PTM-Va or PTM-Vb, at each occurrence, is independently        halo or optionally substituted heterocyclyl, wherein the        substituent, in each occurrence, is independently selected from        alkyl, alkoxy, aminoalkyl, halo, hydroxyl, hydroxyalkyl or        —NR⁷R⁸;    -   R₂ of PTM-Va or PTM-Vb is hydrogen, optionally substituted        cycloalkyl, optionally substituted aryl, optionally substituted        heterocyclyl or —NR⁵R⁶; wherein the substituent is alkyl, amino,        halo or hydroxyl;    -   R₃, of PTM-Va or PTM-Vb at each occurrence, is independently        selected from alkyl or hydroxyl;    -   R₄ of PTM-Va or PTM-Vb at each occurence is independently        selected from hydrogen, halogen, alkyl, aryl, heterocycloalkyi,        heterocycloalkylalkyl, heteroaryl, Y-arylalkyl or —Y-cycloalkyl;        wherein cycloalkyl, aryl, heterocycloalkyi,        heterocycloalkylalkyl, heteroaryl and arylalkyl can be        optionally substituted with hydroxy, alkyl, haloalkyl, cyano or        halo;    -   Y₁ of PTM-Va or PTM-Vb is selected from direct bond, O, —C(O)—        or NR⁹;    -   R₅ and R₆ of PTM-Va or PTM-Vb are independently selected from        hydrogen, optionally substituted alkyl, optionally substituted        acyl, or optionally substituted heterocyclyl, optionally        substituted aryl;    -   R⁹ of PTM-Va or PTM-Vb at each occurence is independently        selected from hydrogen or alkyl;    -   “m” and “n” of PTM-Va or PTM-Vb are independently selected from        0, 1, or 2; and    -   “q” of PTM-Va or PTM-Vb is 0; and    -   “p” of PTM-Va or PTM-Vb is 0 or 1.

In any aspect or embodiment described herein, the group

of PTM-V is

wherein R₂ is as defined in Formula PTM-Va.

In any aspect or embodiment described herein, the Ring Z of PTM-Va orPTM-Vb is aryl or 5- or 6-membered heterocyclyl. In any aspect orembodiment described herein, Ring Z of PTM-V is phenyl, furanyl,thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl,thiazolyl, isothiazolyl, 1H-tetrazolyl, oxadiazolyl, triazolyl, pyridyl,pyrimidinyl, pyrazinyl, pyridazinyl, oxetanyl, imidazolidinyl,pyrrolidinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl,tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl,morpholinyl, thiomorpholinyl, 1,4-dioxanyl, dioxidothiomorpholinyl,oxapiperazinyl, oxapiperidinyl, tetrahydrofuryl, tetrahydropyranyl,tetrahydrothiophenyl or dihydropyranyl; wherein each of which isoptionally substituted with alkyl, alkoxy, halo, hydroxyl, hydroxyalkylor —NR⁵R⁶; R⁵ and R⁶ are independently hydrogen, alkyl or acyl.

In any aspect or embodiment described herein, the Ring Z of PTM-Va orPTM-Vb is phenyl, oxazolyl, furanyl, thienyl or pyridyl; each of whichis optionally substituted with one or more R₁.

In any aspect or embodiment described herein, the

of PTM-Va is

wherein R₃ and “m” are as defined for PTM-Va.

In any aspect or embodiment described herein, the

of PTM-Vb is

wherein R₃ and “m” are as defined for PTM-Vb.

In any aspect or embodiment described herein, the PTM of PTM-Va isselected from: (PTM-V_(B)-1)6′-amino-N-(2-morpholinooxazolo[4,5-b]pyridin-6-yl)-[2,3′-bipyridine]-6-carboxamide;(PTM-V_(B)-2)6′-amino-N-(5-cyclopropyl-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-[2,3′-bipyridine]-6-carboxamidehydrochloride;(PTM-V_(B)-3)N-(5-cyclopropyl-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamidehydrochloride;(PTM-V_(B)-4)N-(2,5-di(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)-6-(1H-pyrazol-4-yl)picolinamidehydrochloride;(PTM-V_(B)-5)N-(2,5-di(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide;(PTM-V_(B)-6)N-(2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)-6-(1H-pyrazol-4-yl)picolinamide;(PTM-V_(B)-7)2-(2-methylpyridin-4-yl)-N-(2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide;(PTM-V_(B)-8)6-chloro-N-(2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)picolinamide;(PTM-V_(B)-9)N-(2,5-di(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)-6-(1-methyl-1H-pyrazol-4-yl)picolinamide;(PTM-V_(B)-10)2-(2-chloropyridin-4-yl)-N-(2,5-di(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide;(PTM-V_(B)-11)(S)-2-(2-methylpyridin-4-yl)-N-(2-morpholino-5-(pyrrolidin-3-ylamino)oxazol[4,5-b]pyridin-6-yl)oxazole-4-carboxamide;(PTM-V_(B)-12)6′-amino-N-(2-morpholinooxazolo[5,4-b]pyridin-5-yl)-[2,31-bipyridine]-6-carboxamide;(PTM-V_(B)-13)6′-amino-N-(2-morpholinothiazolo[4,5-c]pyridin-6-yl)-[2,3′-bipyridine]-6-carboxamide;(PTM-V_(B)-14)6′-amino-N-(2-morpholinothiazolo[5,4-b]pyridin-5-yl)-[2,3′-bipyridine]-6-carboxamide;(PTM-V_(B)-15)2-(2-methylpyridin-4-yl)-N-(2-morpholinothiazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide;(PTM-V_(B)-16)6′-amino-N-(2-morpholinothiazolo[4,5-b]pyridin-6-yl)-[2,3′-bipyridine]-6-carboxamide;(PTM-V_(B)-17)N-(2-morpholinothiazolo[4,5-b]pyridin-6-yl)-6-(1H-pyrazol-4-yl)picolinamide;(PTM-V_(B)-18)3-(4-(aminomethyl)piperidin-1-yl)-5-fluoro-N-(2-morpholinothiazolo[4,5-b]pyridin-6-yl)benzamide;(PTM-V_(B)-19)2-(4-(aminomethyl)piperidin-1-yl)-5-fluoro-N-(2-morpholinothiazolo[4,5-b]pyridin-6-yl)benzamide;(PTM-V_(B)-20)2-(2-methylpyridin-4-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide;(PTM-V_(B)-21)N-(2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)-6-(1H-pyrazol-4-yl)picolinamide;(PTM-V_(B)-22)N-(2,5-di(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)-6-(1H-pyrazol-4-yl)picolinamide;(PTM-V_(B)-23)N-(2,5-di(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide;(PTM-V_(B)-24)N-(2,5-dimorpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide;(PTM-V_(B)-25)N-(5-(4-methylpiperazin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide;(PTM-V_(B)-26)N-(2,5-di(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)-2-(6-methoxypyridin-3-yl)oxazole-4-carboxamide;(PTM-V_(B)-27)N-(2,5-di(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-3-yl)oxazole-4-carboxamide;(PTM-V_(B)-28)N-(2,5-di(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)-2-(2-hydroxypyridin-3-yl)oxazole-4-carboxamide;(PTM-V_(B)-29)2-(2-hydroxypyridin-3-yl)-N-(2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide;(PTM-V_(B)-30)N-(2,5-di(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)-2-(6-hydroxypyridin-3-yl)oxazole-4-carboxamide;(PTM-V_(B)-31)2-(2-methoxypyridin-4-yl)-N-(2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide;(PTM-V_(B)-32)2-(2-methylpyridin-3-yl)-N-(2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide;(PTM-V_(B)-33)2-(3-methylpyridin-4-yl)-N-(2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide;(PTM-V_(B)-34)N-(2,5-di(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)-2-(3-methylpyridin-4-yl)oxazole-4-carboxamide;(PTM-V_(B)-35)2-(6-methylpyridin-3-yl)-N-(2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide;(PTM-V_(B)-36)6-(1-methyl-1H-pyrazol-4-yl)-N-(2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)picolinamide;(PTM-V_(B)-37)N-(2,5-di(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)-2-(6-methylpyridin-3-yl)oxazole-4-carboxamide;(PTM-V_(B)-38)(S)—N-(5-(3-aminopyrrolidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide;(PTM-V_(B)-39)(S)—N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide;(PTM-V_(B)-40)(R)—N-(5-(3-aminopyrrolidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide;(PTM-V_(B)-41)(R)—N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide;(PTM-V_(B)-42)(S)-2-(3-aminopyrrolidin-1-yl)-N-(2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide;(PTM-V_(B)-43)(S)-6-(3-hydroxypyrrolidin-1-yl)-N-(2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)picolinamide;(PTM-V_(B)-44)(S)-6-(3-aminopyrrolidin-1-yl)-N-(2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)picolinamide;(PTM-V_(B)-45)(S)-2-(3-hydroxypyrrolidin-1-yl)-N-(2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide;(PTM-V_(B)-46)(5)-N-(5-cyclopropyl-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(3-hydroxypyrrolidin-1-yl)oxazole-4-carboxamide;(PTM-V_(B)-47)(S)-2-(3-aminopyrrolidin-1-yl)-N-(5-cyclopropyl-2-morpholinooxazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide;(PTM-V_(B)-48)2-(2-methylpyridin-4-yl)-N-(5-(piperidin-1-yl)-2-(pyrrolidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamidehydrochloride;(PTM-V_(B)-49)N-(2-(2,6-dimethylmorpholino)-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamidehydrochloride;(PTM-V_(B)-50)N-(2,5-di(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)-6-(1-methyl-1H-pyrazol-4-yl)picolinamidehydrochloride; (PTM-V_(B)-51)6-(1-methyl-1H-pyrazol-4-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)picolinamide;(PTM-V_(B)-52)N-(2,5-di(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-3-yl)oxazole-4-carboxamidehydrochloride;(PTM-V_(B)-53)N-(2-((2S,6R)-2,6-dimethylmorpholino)-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide;(PTM-V_(B)-54)2-(2-methylpyridin-3-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide;(PTM-V_(B)-55)2-(2-hydroxypyridin-3-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide;(PTM-V_(B)-56)N-(2,5-di(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)-2-(2-methoxypyridin-4-yl)oxazole-4-carboxamide;(PTM-V_(B)-57)2-(6-methoxypyridin-3-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide;(PTM-V_(B)-58)2-(2-methoxypyridin-4-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide;(PTM-V_(B)-59)(S)—N-(5-(3-fluoropiperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide;(PTM-V_(B)-60)2-(6-methylpyridin-3-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide;(PTM-V_(B)-61)2-(3-methylpyridin-4-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide;(PTM-V_(B)-62)(S)-6-(3-aminopyrrolidin-1-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)picolinamide;(PTM-V_(B)-63)(S)-6-(3-hydroxypyrrolidin-1-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)picolinamide;(PTM-V_(B)-64)(S)-6-(3-aminopyrrolidin-1-yl)-N-(2,5-di(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)picolinamide;(PTM-V_(B)-65)(S)—N-(2,5-di(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)-6-(3-hydroxypyrrolidin-1-yl)picolinamide;(PTM-V_(B)-66)(S)-2-(3-aminopyrrolidin-1-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide;(PTM-V_(B)-67)(S)—N-(5-(3-aminopyrrolidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide;(PTM-V_(B)-68)(S)-2-(3-aminopyrrolidin-1-yl)-N-(5-cyclopropyl-2-morpholinothiazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide;(PTM-V_(B)-69)N-(5-cyclopropyl-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide;(PTM-V_(B)-70)(S)-2-(3-hydroxypyrrolidin-1-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide;(PTM-V_(B)-71)(S)—N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide;(PTM-V_(B)-72)(5)-N-(5-cyclopropyl-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-6-(3-hydroxypyrrolidin-1-yl)picolinamide;(PTM-V_(B)-73)(S)—N-(5-cyclopropyl-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(3-hydroxypyrrolidin-1-yl)oxazole-4-carboxamide;(PTM-V_(B)-74)(S)—N-(5-cyclopropyl-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-6-(1-(2-hydroxypropy1)-1H-pyrazol-4-ypicolinamide; (PTM-V_(B)-75)(S)—N-(5-cyclopropyl-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(1-(2-hydroxypropy1)-1H-pyrazol-4-yl)oxazole-4-carboxamide;(PTM-V_(B)-76)N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(6-methoxypyridin-3-yl)oxazole-4-carboxamide;(PTM-V_(B)-77)(S)—N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(6-methoxypyridin-3-yl)oxazole-4-carboxamide;(PTM-V_(B)-78)(R)—N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(6-methoxypyridin-3-yl)oxazole-4-carboxamide;(PTM-V_(B)-79)(S)—N-(5-(azetidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-6-(3-hydroxypyrrolidin-1-yl)picolinamide;(PTM-V_(B)-80)N-(5-(3-hydroxyazetidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide;(PTM-V_(B)-81)(S)—N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-5-(2-methylpyridin-4-yl)thiophene-2-carboxamide;(PTM-V_(B)-82)(S)—N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-5-(2-methylpyridin-4-yl)furan-2-carboxamide;(PTM-V_(B)-83)(S)—N-(5-(3-hydroxypiperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide;(PTM-V_(B)-84)N-(5-(4-hydroxypiperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide;(PTM-V_(B)-85)(R)—N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide;(PTM-V_(B)-86)N-(5-(4-hydroxypiperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-5-(2-methylpyridin-4-yl)furan-2-carboxamide;(PTM-V_(B)-87)N-(5-(azetidin-1-yl)-2-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide;(PTM-V_(B)-88)2-(2-methylpyridin-4-yl)-N-(2-(piperidin-1-yl)-5-(pyrrolidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide;(PTM-V_(B)-89)2-(2-methylpyridin-4-yl)-N-(2-morpholino-5-(pyrrolidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide;(PTM-V_(B)-90)5-(2-methylpyridin-4-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)furan-2-carboxamide;(PTM-V_(B)-91)N-(5-(azepan-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide;(PTM-V_(B)-92)2-(2-aminopyridin-4-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamidehydrochloride;(PTM-V_(B)-93)N-(5-(azetidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide;(PTM-V_(B)-94)(R)—N-(5-(3-hydroxypiperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide;(PTM-V_(B)-95)(R)—N-(5-(3-hydroxypiperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-5-(2-methylpyridin-4-yl)furan-2-carboxamide;(PTM-V_(B)-96) (S)-6-(1-(2-hydroxypropy1)-1H-pyrazol-4-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)picolinamide;(PTM-V_(B)-97)N-(5-(4-fluoropiperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-5-(2-methylpyridin-4-yl)furan-2-carboxamide;(PTM-V_(B)-98)N-(5-(4-fluoropiperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamidehydrochloride;(PTM-V_(B)-99)N-(5-(1-methyl-1H-pyrazol-4-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide;(PTM-V_(B)-100)N-(5-(3-fluorophenyl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide;(PTM-V_(B)-101)N-(5-(4-hydroxypiperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-5-(2-methylpyridin-4-yl)furan-2-carboxamide;(PTM-V_(B)-102)N-(5-(3-fluoropiperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-5-(2-methylpyridin-4-yl)furan-2-carboxamide;(PTM-V_(B)-103)(S)—N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(6-methoxypyridin-3-yl)oxazole-4-carboxamide;(PTM-V_(B)-104)N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide;(PTM-V_(B)-105)(R)—N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(6-methoxypyridin-3-yl)oxazole-4-carboxamide;(PTM-V_(B)-106)N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(6-methoxypyridin-3-yl)oxazole-4-carboxamide;(PTM-V_(B)-107)(S)—N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-5-(2-methylpyridin-4-yl)furan-2-carboxamide;(PTM-V_(B)-108)(S)—N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-5-(2-methylpyridin-4-yl)thiophene-2-carboxamide;(PTM-V_(B)-109)N-(5-(azetidin-1-yl)-2-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide;(PTM-V_(B)-110)2-(2-methylpyridin-4-yl)-N-(2-(piperidin-1-yl)-5-(pyrrolidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide;(PTM-V_(B)-111)5-(2-methylpyridin-4-yl)-N-(2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)furan-2-carboxamide;(PTM-V_(B)-112)N-(5-(azetidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide;(PTM-V_(B)-113)2-(2-methylpyridin-4-yl)-N-(2-morpholino-5-(pyrrolidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide;(PTM-V_(B)-114)N-(5-(4-hydroxypiperidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-5-(2-methylpyridin-4-yl)furan-2-carboxamide;(PTM-V_(B)-115)(R)—N-(5-(3-hydroxypiperidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-5-(2-methylpyridin-4-yl)furan-2-carboxamide;(PTM-V_(B)-116)N-(5-(furan-3-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide;(PTM-V_(B)-117)N-(5-(3-fluoropiperidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide;(PTM-V_(B)-118)N-(5-(4-hydroxypiperidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide;(PTM-V_(B)-119)N-(5-(4-fluoropiperidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide;(PTM-V_(B)-120)(S)—N-(5-(3-aminopiperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide;(PTM-V_(B)-121)2-(2-methylpyridin-4-yl)-N-(2-morpholino-5-(1H-pyrazol-4-yl)thiazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide;(PTM-V_(B)-122)N-(5-(6-fluoropyridin-3-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide;(PTM-V_(B)-123)N-(5-(3-hydroxy-8-azabicyclo[3.2.1]octan-8-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide;(PTM-V_(B)-124)N-(2-(3-hydroxypiperidin-1-yl)-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide;(PTM-V_(B)-125)2-(2-acetamidopyridin-4-yl)-N-(5-(4-hydroxypiperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide;(PTM-V_(B)-126)N-(2-(3-hydroxypiperidin-1-yl)-5-(4-hydroxypiperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide;(PTM-V_(B)-127)2-(2-acetamidopyridin-4-yl)-N-(5-(3-hydroxypiperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide;(PTM-V_(B)-128)2-(2-aminopyridin-4-yl)-N-(5-(3-hydroxypiperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamidehydrochloride; (PTM-V_(B)-129)5-(2-aminopyridin-4-yl)-N-(5-(4-hydroxypiperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)furan-3-carboxamidehydrochloride; (PTM-V_(B)-130)2-(2-aminopyridin-4-yl)-N-(5-(4-hydroxypiperidin-1-yl1)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamidehydrochloride; (PTM-V_(B)-131)2-(2-aminopyridin-4-yl)-N-(5-(4-fluoropiperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamidehydrochloride;(PTM-V_(B)-132)N-(5-(2-fluoropyridin-4-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide;(PTM-V_(B)-133)N-(5-(4-fluoropiperidin-1-yl)-2-(3-hydroxypiperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide;(PTM-V_(B)-134)N-(5-(4-aminopiperidin-1-yl)-2-(3-hydroxypiperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamidehydrochloride; and(PTM-V_(B)-135)N-(5-(2-hydroxypyridin-4-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamidehydrochloride.

In any aspect or embodiment described herein, the PTM is represented byFormula PTM-VI (i.e., Formula PTM-VIa, Formula PTM-VIb, and/or FormulaPTM-VIc, which correspond to Formula I, II, and III, respectively, fromU.S. Patent Application Publication No. 2015/0274708 A1, which isincorporated herein in its entirety for all purposes):

wherein:

-   -   X of PTM-VI is CH or N;    -   a of PTM-VI is 0 or 1;    -   b of PTM-VI is 0 or 1;    -   m of PTM-VI is 0, 1 or 2;    -   Ring A is of PTM-VI (C₃-C₈)cycloalkyl, (C₃-C₈)cycloalkenyl, aryl        or heterocycle optionally substituted with one to three        substituents independently selected from R₁;    -   R₁ of PTM-VI is selected from: H, oxo,        (C═O)_(a)O_(b)(C₁-C₁₀)alkyl, (C═O)_(a)O_(b)-aryl,        (C═O)_(a)O_(b)(C₂-C₁₀)alkenyl, (C═O)_(a)O_(b)(C₂-C₁₀)alkynyl,        CO₂H, halo, OH, O_(b)(C₁-C₆)fluoroalkyl, (C═O)_(a)NR₅R⁶, CN,        (C═O)_(a)O_(b)(C₃-C₈)cycloalkyl, S(O)_(m)NR₅R₆, SH,        S(O)_(m)—(C₁-C₁₀)alkyl and (C═O)_(a)O_(b)-heterocyclyl, said        alkyl, aryl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl are        optionally substituted with one or more substituents selected        from R_(a);    -   R₂ and R₃ of PTM-VI are independently selected from: H,        (C═O)_(a)O_(b)C₁-C₁₀ alkyl, (C═O)_(a)O_(b)aryl, C₂-C₁₀ alkenyl,        C₂-C₁₀ alkynyl, (C═O)_(a)O_(b) heterocyclyl, CO₂H, CN,        O_(b)C₁-C₆ fluoroalkyl, O_(a)(C═O)_(b)NR₅R₆, CHO, (N═O)R₅R⁶,        S(O)_(m)NR₅R₆, SH, S(O)_(m) (C₁-C₁₀)alkyl, (C═O)_(a)O_(b)C₃-C₈        cycloalkyl, optionally substituted with one or more substituents        selected from R₁; or R₂ and R₃ can be taken together with the        nitrogen to which they are attached to form a monocyclic or        bicyclic heterocycle with 3-7 members in each ring and        optionally containing, in addition to the nitrogen, one or two        additional heteroatoms selected from N, O and S, said monocyclic        or bicyclic heterocycle optionally substituted with one or more        substituents selected from R₁;    -   R₄ of PTM-VI is selected from: (C₁-C₆)alkyl and        (C₃-C₆)cycloalkyl, optionally substituted with R_(a);    -   R₅ and R₆ of PTM-VI are independently selected from: H, oxo,        (C═O)_(a)O_(b)(C₁-C₁₀)alkyl, (C═O)_(a)O_(b)-aryl,        (C═O)_(a)O_(b)(C₂-C₁₀)alkenyl, (C═O)_(a)O_(b)(C₂-C₁₀)alkynyl,        CO₂H, O_(b)(C₁-C₆)fluoroalkyl, (C═O)_(a)N(R_(a))₂, CN,        (C═O)_(a)O_(b)(C₃-C₈)cycloalkyl, S(O)_(m) N(R_(a))₂, SH,        S(O)_(m)—(C₁-C₁₀)alkyl and (C═O)_(a)O_(b)-heterocyclyl, said        alkyl, aryl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl are        optionally substituted with one or more substituents selected        from R_(a);    -   R_(a) of PTM-VI is independently selected from R_(b), OH,        (C₁-C₆)alkoxy, halogen, cyclopropyl, CO₂H, CN,        O_(a)(C═O)_(b)(C₁-C₆)alkyl, oxo, and N(R_(b))₂;    -   R_(b) of PTM-VI is independently selected from H and        (C₁-C₆)alkyl; and    -   the PTM-VI is covalently joined to a ULM, a chemical linker        group (L), a CLM, an ILM, a VLM, MLM, a ULM′, a CLM′, a ILM′, a        VLM′, a MLM′, or combination thereof.

In any aspect or embodiment described herein, the PTM-VI is covalentlyjoined to a ULM, a chemical linker group (L), a CLM, an ILM, a VLM, MLM,a ULM′, a CLM′, a ILM′, a VLM′, a MLM′, or combination thereof via an Rgroup (e.g., R₁, R₂, R₃, R₄, R₅, R₆, R₈, or R^(b)).

In any aspect or embodiment described herein, the PTM of PTM-VI isselected from the group consisting of:N-(3-carbamoyl-1-methyl-1H-pyrazol-4-yl)-2′-((cyclopropylmethyl)amino)-[2,4′-bipyridine]-6-carboxamide(PTM-VI-1);N-(3-carbamoyl-1-methyl-1H-pyrazol-4-yl)-6-(1H-pyrrol-1-yl)picolinamide(PTM-VI-2);4-(3-(2-(cyclopropylmethylamino)pyridin-4-yl)benzamido)-1-methyl-1H-pyrazole-3-carboxamide(PTM-VI-3);tert-butyl(6-((3-carbamoyl-1-methyl-1H-pyrazol-4-yl)carbamoyl)-[2,4′-bipyridin]-2′-yl)carbamate(PTM-VI-4);N-(3-carbamoyl-1-methyl-1H-pyrazol-4-yl)-2′-(cyclopropylmethylamino)-2,4′-bipyridine-4-carboxamide(PTM-VI-5);2′-amino-N-(3-carbamoyl-1-methyl-1H-pyrazol-4-yl)-[2,4′-bipyridine]-6-carboxamide(PTM-VI-6);N-(3-carbamoyl-1-methyl-1H-pyrazol-4-yl)-2′-(cyclopropylmethylamino)-3,4′-bipyridine-5-carboxamide(PTM-VI-7);N-(5-carbamoyl-1-methyl-1H-pyrazol-4-yl)-2′-(cyclopropylmethylamino)-2,4′-bipyridine-6-carboxamide(PTM-VI-8);N-(3-carbamoyl-1-methyl-1H-pyrazol-4-yl)-6-morpholinopicolinamide(PTM-VI-9);N-(3-carbamoyl-1-methyl-1H-pyrazol-4-yl)-6-(piperazin-1-yl)picolinamide(PTM-VI-10):N-(3-carbamoyl-1-methyl-1H-pyrazol-4-yl)-2,4′-bipyridine-6-carboxamide(PTM-VI-11);N-(3-carbamoyl-1-methyl-1H-pyrazol-4-yl)-[2,3′-bipyridine]-6-carboxamide(PTM-VI-12):N-(3-carbamoyl-1-methyl-1H-pyrazol-4-yl)-6-(3-methoxyphenyl)picolinamide(PTM-VI-13);N-(3-carbamoyl-1-methyl-1H-pyrazol-4-yl)-6-phenylpicolinamide(PTM-VI-14);N-(3-carbamoyl-1-methyl-1H-pyrazol-4-yl)-2′-((2-methoxyethyl)amino)-[2,4′-bipyridine]-6-carboxamide(PTM-VI-15);N-(3-carbamoyl-1-methyl-1H-pyrazol-4-yl)-2′-((2,2-difluoroethyl)amino)-[2,4′-bipyridine]-6-carboxamide (PTM-VI-16);N-(3-carbamoyl-1-methyl-1H-pyrazol-4-yl)-2′-(((tetrahydro-2H-pyran-4-yl)methyl)amino)-[2,4′-bipyridine]-6-carboxamide(PTM-VI-17);N-(3-carbamoyl-1-methyl-1H-pyrazol-4-yl)-2′-((2,2,2-trifluoroethyl)amino)-[2,4′-bipyridine]-6-carboxamide(PTM-VI-18):N-(3-carbamoyl-1-methyl-1H-pyrazol-4-yl)-2-(2-((cyclopropylmethyl)amino)pyridin-4-yl)pyrimidine-4-carboxamide(PTM-VI-19);N-(3-carbamoyl-1-methyl-1H-pyrazol-4-yl)-2′-methoxy-[2,3′-bipyridine]-6-carboxamide(PTM-VI-20);N-(3-carbamoyl-1-methyl-1H-pyrazol-4-yl)-6-(3-(trifluoromethoxy)phenyl)picolinamide(PTM-V 1-21);N-(3-carbamoyl-1-methyl-1H-pyrazol-4-yl)-6-(thiophen-3-yl)picolinamide(PTM-VI-22);N-(3-carbamoyl-1-methyl-1H-pyrazol-4-yl)-6′-morpholino-[2,3′-bipyridine]-6-carboxamide(PTM-VI-23);N-(3-carbamoyl-1-methyl-1H-pyrazol-4-yl)-6-(3-(methylcarbamoyl)phenyl)picolinamide(PTM-VI-24);N-(3-carbamoyl-1-methyl-1H-pyrazol-4-yl)-6-(1-methyl-1H-pyrazol-4-yl)picolinamide(PTM-VI-25);N-(3-carbamoyl-1-methyl-1H-pyrazol-4-yl)-6-(1,1-dioxido-3,6-dihydro-2H-thiopyran-4-yl)picolinamide(PTM-V 1-26);N-(3-carbamoyl-1-methyl-1H-pyrazol-4-yl)-6-(5,6-dihydro-2H-pyran-3-yl)picolinamide(PTM-VI-27);N-(3-carbamoyl-1-methyl-1H-pyrazol-4-yl)-6′-cyclopropyl-[2,3′-bipyridine]-6-carboxamide(PTM-VI-28);N-(3-carbamoyl-1-methyl-1H-pyrazol-4-yl)-5′-chloro-[2,3′-bipyridine]-6-carboxamide(PTM-VI-29);N-(3-carbamoyl-1-methyl-1H-pyrazol-4-yl)-6-(3,6-dihydro-2H-pyran-4-yl)picolinamide(PTM-VI-30);N-(3-carbamoyl-1-methyl-1H-pyrazol-4-yl)-4′-chloro-[2,3′-bipyridine]-6-carboxamide(PTM-VI-31);N-(3-carbamoyl-1-methyl-1H-pyrazol-4-yl)-1′-methyl-6′-oxo-1′,2′,3′,6′-tetrahydro-[2,4′-bipyridine]-6-carboxamide(PTM-VI-32);N-(3-carbamoyl-1-methyl-1H-pyrazol-4-yl)-1′-methyl-1′,2′,5′,6′-tetrahydro-[2,3′-bipyridine]-6-carboxamide(PTM-VI-33); 2′-((cyclopropylmethyl)amino)-N-(1-methyl-3-(((1-methylpyrrolidin-3-yl)methyl)carbamoyl)-1H-pyrazol-4-yl)-[2,4′-bipyridine]-6-carboxamide(PTM-VI-34);2′-((cyclopropylmethyl)amino)-N-(1-methyl-3-((2-(pyrrolidin-1-yl)ethyl)carbamoyl)-1H-pyrazol-4-yl)-[2,4′-bipyridine]-6-carboxamide(PTM-VI-35);N-(3-(((1H-imidazol-2-yl)methyl)carbamoyl)-1-methyl-1H-pyrazol-4-yl)-2′-((cyclopropylmethyl)amino)-[2,4′-bipyridine]-6-carboxamide(PTM-VI-36);2′-((cyclopropylmethyl)amino)-N-(3-((5-(dimethylamino)pentyl)carbamoyl)-1-methyl-1H-pyrazol-4-yl)-[2,4′-bipyridine]-6-carboxamide(PTM-VI-37);2′-((cyclopropylmethyl)amino)-N-(1-methyl-3-((2-(pyridin-2-yl)ethyl)carbamoyl)-1H-pyrazol-4-yl)-[2,4′-bipyridine]-6-carboxamide(PTM-VI-38);2′-((cyclopropylmethyl)amino)-N-(1-methyl-3-(4-methylpiperazine-1-carbonyl)-1H-pyrazol-4-yl)-[2,4′-bipyridine]-6-carboxamide(PTM-VI-39);2′-((cyclopropylmethyl)amino)-N-(3-((3-(dimethylamino)propyl)carbamoyl)-1-methyl-1H-pyrazol-4-yl)-[2,4′-bipyridine]-6-carboxamide(PTM-VI-40);2′-((cyclopropylmethyl)amino)-N-(1-methyl-3-(morpholine-4-carbonyl)-1H-pyrazol-4-yl)-[2,4′-bipyridine]-6-carboxamide(PTM-VI-41);N-(3-(3-(aminomethyl)azetidine-1-carbonyl)-1-methyl-1H-pyrazol-4-yl)-2′-((cyclopropylmethyl)amino)-[2,4′-bipyridine]-6-carboxamide(PTM-VI-42);2′-((cyclopropylmethyl)amino)-N-(1-methyl-3-(pyrimidin-5-ylcarbamoyl)-1H-pyrazol-4-yl)-[2,4′-bipyridine]-6-carboxamide(PTM-VI-43); 2′-((cyclopropylmethyl)amino)-N-(1-methyl-3-((2-(pyrazin-2-yl)ethyl)carbamoyl)-1H-pyrazol-4-yl)-[2,4′-bipyridine]-6-carboxamide(PTM-VI-44);2′-((cyclopropylmethyl)amino)-N-(3-(((1,1-dioxidotetrahydrothiophen-3-yl)methyl)carbamoyl)-1-methyl-1H-pyrazol-4-yl)-[2,4′-bipyridine]-6-carboxamide (PTM-VI-45);2′-((cyclopropylmethyl)amino)-N-(3-((3S,4S)-3-(dimethylamino)-4-hydroxypyrrolidine-1-carbonyl)-1-methyl-1H-pyrazol-4-yl)-[2,4′-bipyridine]-6-carboxamide(PTM-VI-46);2′-((cyclopropylmethyl)amino)-N-(1-methyl-3-((pyrimidin-4-ylmethyl)carbamoyl)-1H-pyrazol-4-yl)-[2,4′-bipyridine]-6-carboxamide(PTM-VI-47);N-(3-(((1,3,4-thiadiazol-2-yl)methyl)carbamoyl)-1-methyl-1H-pyrazol-4-yl)-2′-((cyclopropylmethyl)amino)-[2,4′-bipyridine]-6-carboxamide(PTM-VI-48);2′-((cyclopropylmethyl)amino)-N-(1-methyl-3-(((1-methylpiperidin-3-yl)methyl)carbamoyl)-1H-pyrazol-4-yl)-[2,4′-bipyridine]-6-carboxamide(PTM-VI-49);N-(3-((2-(1H-pyrazol-1-yl)ethyl)carbamoyl)-1-methyl-1H-pyrazol-4-yl)-2′-((cyclopropylmethyl)amino)-[2,4′-bipyridine]-6-carboxamide(PTM-VI-50); and2′-((cyclopropylmethyl)amino)-N-(1-methyl-3-((tetrahydrofuran-3-yl)carbamoyl)-1H-pyrazol-4-yl)-[2,4′-bipyridine]-6-carboxamide(PTM-VI-51).

In any aspect or embodiment described herein, the PTM of PTM-VI isselected from the group consisting of:N-(3-carbamoyl-1-methyl-1H-pyrazol-4-yl)-2′-((cyclopropylmethyl)amino)-[2,4′-bipyridine]-6-carboxamide(PTM-VI-1);N-(3-carbamoyl-1-methyl-1H-pyrazol-4-yl)-[2,3′-bipyridine]-6-carboxamide(PTM-VI-12);N-(3-carbamoyl-1-methyl-1H-pyrazol-4-yl)-2′-((2-methoxyethyl)amino)-[2,4′-bipyridine]-6-carboxamide(PTM-VI-15);N-(3-carbamoyl-1-methyl-1H-pyrazol-4-yl)-2′-((2,2-difluoroethyl)amino)-[2,4′-bipyridine]-6-carboxamide(PTM-VI-16);N-(3-carbamoyl-1-methyl-1H-pyrazol-4-yl)-2′-((2,2,2-trifluoroethyl)amino)-[2,4′-bipyridine]-6-carboxamide(PTM-VI-18);N-(3-carbamoyl-1-methyl-1H-pyrazol-4-yl)-6-(thiophen-3-yl)picolinamide(PTM-VI-22);N-(3-carbamoyl-1-methyl-1H-pyrazol-4-yl)-6′-cyclopropyl-[2,3′-bipyridine]-6-carboxamide(PTM-VI-28);N-(3-carbamoyl-1-methyl-1H-pyrazol-4-yl)-1′-methyl-6′-oxo-1′,2′,3′,6′-tetrahydro-[2,4′-bipyridine]-6-carboxamide(PTM-VI-32);N-(3-(3-(aminomethyl)azetidine-1-carbonyl)-1-methyl-1H-pyrazol-4-yl)-2′-((cyclopropylmethyl)amino)-[2,4′-bipyridine]-6-carboxamide(PTM-VI-42); and2′-((cyclopropylmethyl)amino)-N-(1-methyl-3-(((1-methylpiperidin-3-yl)methyl)carbamoyl)-1H-pyrazol-4-yl)-[2,4′-bipyridine]-6-carboxamide(PTM-VI-49).

In any aspect or embodiment described herein, the heterocyclyl of PTM-VIis independently selected from benzoimidazolyl, benzoimidazolonyl,benzofuranyl, benzofurazanyl, benzopyrazolyl, benzotriazolyl,benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl,furanyl, imidazolyl, indolinyl, indolyl, indolazinyl, indazolyl,isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl,naphthpyridinyl, oxadiazolyl, oxazolyl, oxazoline, isoxazoline,oxetanyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridopyridinyl,pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, quinazolinyl, quinolyl,quinoxalinyl, tetrahydropyranyl, tetrazolyl, tetrazolopyridyl,thiadiazolyl, thiazolyl, thienyl, triazolyl, azetidinyl, 1,4-dioxanyl,hexahydroazepinyl, piperazinyl, piperidinyl, pyridin-2-onyl,pyrrolidinyl, morpholinyl, thiomorpholinyl, dihydrobenzoimidazolyl,dihydrobenzofuranyl, dihydrobenzothiophenyl, dihydrobenzoxazolyl,dihydrofuranyl, dihydroimidazolyl, dihydroindolyl, dihydroisooxazolyl,dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl,dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl,dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl,dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl,dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl,methylenedioxybenzoyl, tetrahydrofuranyl, and tetrahydrothienyl, andN-oxides thereof, optionally substituted with one to three substituentsindependently selected from R_(a).

In any aspect or embodiment described herein, the Ring A of PTM-VI isaryl, heteroaryl or heterocycle optionally substituted with one to threesubstituents independently selected from R₁. For example, Ring A may beselected from the group consisting of phenyl, benzoimidazolyl,benzoimidazolonyl, benzofuranyl, benzofurazanyl, benzopyrazolyl,benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl,cinnolinyl, furanyl, imidazolyl, indolinyl, indolyl, indolazinyl,indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl,isoxazolyl, naphthpyridinyl, oxadiazolyl, oxazolyl, oxazoline,isoxazoline, oxetanyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl,pyridopyridinyl, pyridazinyl, pyridyl, pyrimidyl, pyrrolyl,quinazolinyl, quinolyl, quinoxalinyl, tetrahydropyranyl, tetrazolyl,tetrazolopyridyl, thiadiazolyl, thiazolyl, thienyl, triazolyl,azetidinyl, 1,4-dioxanyl, hexahydroazepinyl, piperazinyl, piperidinyl,pyridin-2-onyl, pyrrolidinyl, morpholinyl and thiomorpholinyl, which areoptionally substituted with one to three substituents independentlyselected from R₁.

In any aspect or embodiment described herein, the R₁ of PTM-VI isindependently selected from: H, oxo, (C═O)_(a)(C₁-C₁₀)alkyl,(C═O)_(a)-aryl, CO₂H, halo, OH, O_(b)(C₁-C₆)fluoroalkyl, (C═O)_(a)NR₅R⁶,CN, (C═O)_(a)(C₃-C₈)cycloalkyl and (C═O)_(a)O_(b)-heterocyclyl, saidalkyl, aryl, cycloalkyl, and heterocyclyl are optionally substitutedwith one or more substituents selected from R_(a).

In any aspect or embodiment described herein, the R₂ and R₃ of PTM-VIare independently selected from: H and C₁-C₆ alkyl, optionallysubstituted with one or more substituents selected from R₁; or R₂ and R₃can be taken together with the nitrogen to which they are attached toform a monocyclic heterocycle with 3-7 members in each ring andoptionally containing, in addition to the nitrogen, one or twoadditional heteroatoms selected from N, O and S, said monocyclic orbicyclic heterocycle optionally substituted with one or moresubstituents selected from R₁.

In any aspect or embodiment described herein, the R₄ of PTM-VI isselected from (C₁-C₆)alkyl optionally substituted with OH, methoxy andhalogen.

In any aspect or embodiment described herein, the R₅ and R₆ of PTM-VIare independently selected from: H, (C═O)_(a)(C₁-C₁₀)alkyl,(C═O)_(a)(C₃-C₈)cycloalkyl, (C═O)_(a)-aryl, (C═O)_(a)-heterocyclyl and(C═O)_(a)N(R_(a))₂.

In any aspect or embodiment described herein, the R_(a) of PTM-VI isindependently selected from R_(b), OH, (C₁-C₆)alkoxy, halogen,cyclopropyl, CO₂H, CN, O_(a)(C═O)_(b)(C₁-C₆)alkyl, oxo, and N(R_(b))₂.

In any aspect or embodiment described herein, the R_(b) of PTM-VI isindependently selected from H and methyl.

In an embodiment, the PTM is represented by Formula PTM-VII (i.e.,Formulas PTM-VIIa, PTM-VIIb, PTM-VIIc, PTM-VIId, PTM-VIIe, PTM-VIIf,PTM-VIIg, PTM-VIIh, PTM-VIIi, PTM-VIIj, PTM-VIIk and/or PTM-VIIm, whichcorrespond to Formulas Ia, Ib, Ic, IIa, IIb, IIc, IId, IIe, IIf, IIg,III, and IIIa respectively, from U.S. Patent Application Publication No.2015/0284405 A1, which is incorporated herein in its entirety for allpurposes):

wherein:

-   -   X and X′ of PTM-VII are each independently CR⁸, N or —N⁺—O⁻; Y        is independently N, N⁺—O⁻ or CR^(8′); provided that at least one        of X, X′ or Y is neither N nor —N⁺—O⁻ and that no more than one        of X, X′ or Y is —N⁺—O⁻;    -   R¹ of PTM-VII is C₁-C₆alkyl; C₂-C₆alkenyl; C₂-C₆alkynyl;        —(CR^(3a)R^(3b))_(m)-(3- to 7-membered cycloalkyl);        —(CR^(3a)R^(3b))_(m)-(3- to 7-membered heterocycloalkyl) having        one to three heteroatoms; —(CR^(3a)R^(3b))_(m)-(5- to        10-membered heteroaryl), having one to three heteroatoms; or        —(CR^(3a)R^(3b))_(m)—C₆-C₁₂aryl; wherein said alkyl, alkenyl,        alkynyl, cycloalkyl, heterocycloalkyl, heteroaryl or aryl is        optionally substituted with one to five halogen, deuterium,        —OR⁵, —SR⁵, —NR^(11a)R^(11b), cyano, C₁-C₆alkyl, C₃-C₆cycloalkyl        or —C₁-C₆alkoxy;    -   R² of PTM-VII is —(CR^(3a)R^(3b))_(m)-(3- to 10-membered        cycloalkyl); —(CR^(3a)R^(3b))_(m)-(3- to 10-membered        heterocycloalkyl) having one to three heteroatoms;        —(CR^(3a)R^(3b))_(m)-(5- to 10 membered heteroaryl) having one        to three heteroatoms; or —(CR^(3a)R^(3b))_(m)—C₆-C₁₂aryl;        wherein said cycloalkyl, heterocycloalkyl, heteroaryl or aryl is        optionally substituted with one to five R⁴; and wherein, if the        heteroatom on said heterocycloalkyl and heteroaryl is N, said N        is optionally substituted with R^(4′); or R² is C₁-C₆alkyl,        wherein said alkyl is optionally substituted with NH₂, OH or        cyano;    -   R^(3a) and R^(3b) of PTM-VII for each occurrence are        independently hydrogen or C₁-C₃alkyl;    -   R⁴ of PTM-VII for each occurrence is independently a bond,        deuterium, halogen, cyano, C₁-C₆alkyl, C₂-C₆alkenyl, oxo, —OR⁵,        —SR⁵, —S(O)R⁹, —S(O)₂R⁹, —NR^(11a)R^(11b), C(O)R¹⁰,        —(CR^(3a)R^(3b))_(n)-(3- to 7-membered cycloalkyl),        —(CR^(3a)R^(3b))_(n)-(4- to 10-membered heterocycloalkyl),        having one to three heteroatoms, —(CR^(3a)R^(3b))_(n)-(5- to 10        membered heteroaryl), having one to three heteroatoms, or        —(CR^(3a)R^(3b))_(n)—C₆-C₁₂aryl wherein said alkyl, cycloalkyl,        heterocycloalkyl, heteroaryl or aryl is each optionally and        independently substituted with one to five deuterium, halogen,        OR⁵, —SR⁵, —NR^(11a)R^(11b) cyano, C₁-C₆alkyl, C₃-C₆cycloalkyl        or C₁-C₆alkoxy; or two R⁴ taken together with the respective        carbons to which each are bonded form a 3- to 6-membered        cycloalkyl or 4- to 6-membered heterocycloalkyl, wherein said        cycloalkyl or heterocycloalkyl is optionally substituted with        one to three halogen, deuterium, —OR⁵, —SR⁵, —NR^(11a)R^(11b),        cyano or C₁-C₆alkyl or C₁-C₆alkoxy, wherein the alkyl or alkoxy        is optionally substituted with halogen, deuterium, —OR⁵, —SR⁵,        —NR^(11a)R^(11b) or cyano; and wherein, if a heteroatom on said        heterocycloalkyl is N, said N is optionally substituted with        R^(4′);    -   R^(4′) of PTM-VII is independently C₁-C₆alkyl, C₂-C₆alkenyl,        —C(O)R¹⁰, —S(O)₂R⁹, (CR^(3a)R^(3b))_(n)-(3- to 7-membered        cycloalkyl), —(CR^(3a)R^(3b))_(n)-(4- to 10-membered        heterocycloalkyl) or C(O)(CH₂)_(t)CN; wherein said alkyl,        alkenyl, cycloalkyl, or heterocycloalkyl is each optionally and        independently substituted with one to five deuterium, halogen,        OH, cyano or C₁-C₆alkoxy; or R⁴ and R^(4′) taken together with        the respective atoms to which each are bonded form a 3- to        6-membered cycloalkyl or 4- to 6-membered heterocycloalkyl,        wherein said cycloalkyl or heterocycloalkyl is optionally        substituted with one to three halogen, deuterium, —OR⁵, —SR⁵,        cyano, C₁-C₆alkyl or C₁-C₆alkoxy, wherein the alkyl or alkoxy is        optionally substituted with halogen, deuterium, —OR⁵, —SR⁵,        NR^(11a)R^(11b), or cyano;    -   R^(4a) and R^(4b) of PTM-VII are each independently hydrogen,        deuterium, fluoro, OH, —OR⁵, methyl, ethyl, vinyl, cyclopropyl        or propyl, optionally substituted with one to five deuterium,        fluoro, methoxy or OH;    -   R^(4c) and R^(4d) of PTM-VII for each occurrence are        independently and optionally halogen, OH, deuterium, C₁-C₆alkyl,        C₂-C₆alkenyl, —OR⁵, —(CR^(3a)R^(3b))_(n)-(3- to 6-membered        cycloalkyl), or —(CR^(3a)R^(3b))_(n)-(4- to 6-membered        heterocycloalkyl) wherein said alkyl, cycloalkyl and        heterocycloalkyl are each optionally and independently        substituted with one to five deuterium, halogen, OH, cyano, or        C₁-C₆alkoxy; NH₂; or R^(4c) and R^(4d) taken together with the        carbons to which they are bonded form a 4- to 7-membered        heterocycloalkyl or a 3- to 7-membered cycloalkyl, wherein said        heterocycloalkyl or cycloalkyl is optionally substituted with        one to three fluoro, C₁-C₃alkyl or C₁-C₃fluoroalkyl;    -   or R^(4a) and R^(4c) of PTM-VII taken together with the carbon        to which they are bonded form a 4- to 7-membered        heterocycloalkyl or a 3- to 7-membered cycloalkyl, wherein said        heterocycloalkyl or cycloalkyl is optionally substituted with        one to three fluoro, C₁-C₃alkyl or C₁-C₃fluoroalkyl;    -   R⁵ of PTM-VII is independently hydrogen or C₁-C₆alkyl, wherein        said alkyl is optionally substituted with halogen, deuterium,        C₁-C₆alkoxy, C₁-C₆alkylthiolyl, —NR^(11a)R^(11b), cyano,        C₁-C₆alkyl or C₃-C₆cycloalkyl; or two R⁵ taken together with the        oxygen atoms to which they are bonded form a 5- or 6-membered        heterocycloalkyl;    -   R⁶ of PTM-VII is —C(O)NHR⁷, CO₂R⁷ or cyano;    -   R⁷ of PTM-VII is hydrogen or C₁-C₆alkyl;    -   each R⁸ of PTM-VII is independently hydrogen, halogen, cyano,        —OR⁵, —SR⁵, —C₁-C₆alkyl, C₃-C₆cycloalkyl, 3- to 10-membered        heterocycloalkyl or 5- to 6-membered heteroaryl or aryl, wherein        said alkyl, cycloalkyl, heterocycloalkyl, heteroaryl or aryl is        optionally substituted with one to three halogen,        —NR^(11a)R^(11b), —OR⁵, —SR⁵, cyano, C₁-C₃alkyl, —C(O)R¹⁰ or        oxo;    -   R^(8′) of PTM-VII is hydrogen, deuterium, halogen, cyano, —OR⁵,        —SR⁵ or —NR^(11a)NR^(11b);    -   R⁹ of PTM-VII is —(CR^(3a)R^(3b))_(p)(C₁-C₃alkyl),        —(CR^(3a)R^(3b))_(p)(4- to 6-membered cycloalkyl),        (CR^(3a)R^(3b))_(p)(4- to 6-membered heterocycloalkyl) or        —(CR^(3a)R^(3b))_(p)(C₅-C₉aryl), wherein said alkyl, cycloalkyl,        heterocycloalkyl or aryl is each optionally substituted with        fluoro or C₁-C₃alkyl;    -   R¹⁰ of PTM-VII is C₁-C₆alkyl, wherein said alkyl is optionally        substituted with deuterium, halogen, OH, C₁-C₆alkoxy or cyano;    -   R^(11a) and R^(11b) of PTM-VII are each independently hydrogen        or C₁-C₆alkyl, wherein said alkyl is optionally substituted with        deuterium, C₁-C₆alkoxy or cyano; and if C₂-C₆alkyl, said alkyl        is optionally substituted with deuterium, C₁-C₆alkoxy, cyano,        halogen or OH;    -   m of PTM-VII is independently 0, 1, 2 or 3;    -   n of PTM-VII is independently 0, 1, 2 or 3;    -   p of PTM-VII is independently 0 or 1;    -   t of PTM-VII is 1, 2 or 3; and    -   the PTM-VII is covalently joined to a ULM, a chemical linker        group (L), a CLM, an ILM, a VLM, MLM, a ULM′, a CLM′, a ILM′, a        VLM′, a MLM′, or combination thereof.

In any aspect or embodiment described herein, the PTM-VII is covalentlyjoined to a ULM, a chemical linker group (L), a CLM, an ILM, a VLM, MLM,a ULM′, a CLM′, a ILM′, a VLM′, a MLM′, or combination thereof via an Rgroup (e.g., R¹, R², R^(3a), R^(3b), R⁴, R^(4′), R^(4a), R^(4b), R^(4c),R^(4d), R⁵, R⁶, R⁷, R⁸, R^(8′), R⁹, R¹⁰, R^(11a), or R^(11b)).

In any aspect or embodiment described herein, the PTM of PTM-VIIcomprises one of the following combinations: X is N, X′ is CR⁸ and Y isCR^(8′); X is N, X′ is N and Y is CR^(8′); X is N, X′ is CR⁸ and Y is N;X is CR⁸, X′ and Y are N; X and X′ are CR⁸ and Y is N; X is CR⁸ and Y isCR^(8′) and X′ is N; or X and X′ are CR⁸ and Y is CR^(8′). In any aspector embodiments described herein, R⁶ of PTM-VII is —C(O)NHR⁷, —CO₂R⁷ orcyano; and R⁷ is hydrogen

In any aspect or embodiment described herein, the PTM of PTM-VII (e.g.,PTM-VIId, PTM-VIIe, PTM-VIIf, PTM-VIIg, PTM-VIIh, PTM-VIIi, PTM-VIIj)comprise at least one of:

-   -   R¹ of PTM-VII is C₁-C₆alkyl; C₂-C₆alkenyl; C₂-C₆alkynyl;        —(CR^(3a)R^(3b))_(m)-(3- to 7-membered cycloalkyl); or        —(CR^(3a)R^(3b))_(m)-(3- to 7-membered heterocycloalkyl) having        one to three heteroatoms; wherein said alkyl, alkenyl, alkynyl,        cycloalkyl or heterocycloalkyl is optionally substituted with        one to five halogen, deuterium, —OR⁵, —SR⁵, —NR^(11a)R^(11b),        cyano, C₁-C₆alkyl, C₃-C₆cycloalkyl or —C₁-C₆alkoxy;    -   R² of PTM-VII is —(CR^(3a)R^(3b))_(m)-(3- to 7-membered        cycloalkyl), wherein said cycloalkyl is optionally substituted        with one to four R⁴; —(CR^(3a)R^(3b))_(m)-(3- to 7-membered        heterocycloalkyl) having one to three heteroatoms, wherein said        heterocycloalkyl is optionally substituted at a carbon atom with        one to five R⁴ and wherein, if the heteroatom is N, said N is        optionally substituted with R^(4′); or R² is C₁-C₆alkyl, wherein        said alkyl is optionally substituted with NH₂, cyano or halogen;    -   R^(3a) and R^(3b) of PTM-VII are each independently hydrogen or        C₁-C₃alkyl;    -   R⁴ of PTM-VII for each occurrence is independently and        optionally halogen, cyano, C₁-C₆alkyl, C₂-C₆alkenyl, oxo, —OR⁵,        —SR⁵, —S(O)R⁹, —S(O)₂R⁹, —C(O)R¹⁰, (CR^(3a)R^(3b))_(n)-(3- to        7-membered cycloalkyl) or —(CR^(3a)R^(3b))_(n)-(4- to 7-membered        heterocycloalkyl) wherein said alkyl, cycloalkyl or        heterocycloalkyl is each optionally and independently        substituted with one to five deuterium, halogen, —OR⁵, —SR⁵,        NR^(11a)R^(11b), cyano, C₁-C₆alkyl, C₃-C₆cycloalkyl, C₁-C₆alkoxy        or NR^(11a)R^(11b); or two R⁴ taken together with the respective        carbons to which each are bonded form a 3- to 6-membered        cycloalkyl or 4- to 6-membered heterocycloalkyl, wherein said        cycloalkyl or heterocycloalkyl is optionally substituted with        one to three halogen, deuterium, —OR⁵, —SR⁵, —NR^(11a)R^(11b),        cyano or C₁-C₆alkyl or C₁-C₆alkoxy, wherein the alkyl or alkoxy        is optionally substituted with halogen, deuterium, —OR⁵,        —NR^(11a)R^(11b), or cyano; and wherein, if a heteroatom on said        heterocycloalkyl is N, said N is optionally substituted with        R^(4′);    -   R^(4′) of PTM-VII is independently C₁-C₆alkyl, C₂-C₆alkenyl,        —S(O)R⁹, —S(O)₂R⁹, C(O)R¹⁰, C(O)(CH₂)_(t)CN; wherein said alkyl        is optionally substituted with NH₂, cyano or halogen        —(CR^(3a)R^(3b))_(n)-(3- to 7-membered cycloalkyl), or        (CR^(3a)R^(3b))_(n)-(4- to 10-membered heterocycloalkyl),        wherein said alkyl, alkenyl, cycloalkyl, or heterocycloalkyl is        each optionally and independently substituted with one to five        deuterium, halogen, OH, cyano or C₁-C₆alkoxy; or R⁴ and R^(4′)        taken together with the respective atoms to which each are        bonded form a 3- to 6-membered cycloalkyl or 4- to 6-membered        heterocycloalkyl, wherein said cycloalkyl or heterocycloalkyl is        optionally substituted with one to three halogen, deuterium,        —OR⁵, —SR⁵, —NR^(11a)R^(11b), cyano, C₁-C₆alkyl or C₁-C₆alkoxy,        wherein the alkyl or alkoxy is optionally substituted with        halogen, deuterium, —OR⁵, SR⁵, —NR^(11a)R^(11b) or cyano;    -   R⁵ of PTM-VII is hydrogen or C₁-C₆alkyl, wherein said alkyl is        optionally substituted with halogen;    -   R⁶ of PTM-VII is —C(O)NHR⁷ or cyano;    -   R⁷ of PTM-VII is hydrogen or C₁-C₆alkyl;    -   R⁸ of PTM-VII is independently hydrogen, halogen, cyano,        —NR^(11a)R^(11b), C₁-C₆alkyl, 5- to 6-membered heteroaryl or 5-        to 6-membered aryl, wherein said alkyl or heteroaryl or aryl is        optionally substituted with one to three halogen,        —NR^(11a)R^(11b), C₁-C₃ alkyl or oxo;    -   R^(8′) of PTM-VII is hydrogen, deuterium, halogen, cyano, —OR⁵        or NR^(11a)NR^(11b);    -   R⁹ of PTM-VII is —(CR^(3a)R^(3b))_(p)(C₁-C₃alkyl),        —(CR^(3a)R^(3b))(4- to 6-membered cycloalkyl),        (CR^(3a)R^(3b))_(p)(4- to 6-membered heterocycloalkyl) or        —(CR^(3a)R^(3b))_(p)(C₆-C₉aryl), wherein said alkyl, cycloalkyl,        heterocycloalkyl or aryl is each optionally substituted with        fluoro or C₁-C₃alkyl;    -   R¹⁰ of PTM-VII is C₁-C₆alkyl, wherein said alkyl is optionally        substituted with fluoro or cyano;    -   R^(11a) and R^(11b) of PTM-VII are each independently hydrogen        or C₁-C₆alkyl, wherein said alkyl is optionally substituted with        OH;    -   m of PTM-VII is independently 0, 1 or 2;    -   n of PTM-VII is independently 0 or 1;    -   p of PTM-VII is independently 0 or 1;    -   t of PTM-VII is 0, 1, 2 or 3;    -   or a combination thereof.

In any aspect or embodiment described herein, the R¹ of PTM-VII isfluoromethyl; difluoromethyl; trifluoromethyl; methyl, ethyl, propyl orisopropyl, each optionally substituted with one to three fluoro ordeuterium; allene, propargyl, cyclopropyl, cyclobutyl, cyclopentyl,cyclopropylmethyl, oxetane or tetrahydrofuran, each of which isoptionally substituted with fluoro or C₁-C₃ alkyl.

In any aspect or embodiment described herein, the R² of PTM-VII isselected from pyrrolidinyl, pyrrolidin-2-onyl, piperidinyl,piperidin-2-onyl, octahydro-1H-pyrrolo[3,4-c]pyridinyl, oxazolidinyl,oxazolidin-2-onyl, 1,3-oxazinan-2-onyl, imidazolidinyl,imidazolidin-2-onyl, morpholinyl, morpholin-3-onyl, thiazyl, isothiazyl,isothiazolidine-1,1-dioxidyl, 1,2-thiazinane 1,1-dioxidyl,hexahydrocyclopenta[b]pyrrol-2(1H)-onyl, octahydrocyclopenta[c]pyrrolyl,azetidinyl, hexahydro-1H-indol-2(3H)-onyl, octahydro-1H-isoindolyl,azepanyl, tetrahydrofuranyl, 1,3-dioxolanyl, oxetanyl, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, 4-azepanyl, 1,4-oxazepanyl,tetrahydro-2H-pyranyl, 6,7-dihydro-5H-pyrrolo[1,2-a]imidazolyl,cyclohex-2-enyl, or 1,2,3,4-tetrahydroisoquinolinyl; wherein said alkyl,cycloalkyl or heterocycloalkyl is optionally substituted with one tofour R⁴.

In any aspect or embodiment described herein, the R⁴ of PTM-VII isselected from F, Cl, OH; C₁-C₃alkyl, optionally substituted with one tofive deuterium, Cl, F, OH, C₁-C₃alkyl, C₁-C₃alkoxy; or two R⁴ takentogether with the respective carbons to which each are bonded form acyclopropyl, cyclobutyl or cyclopentyl, wherein said cyclopropyl,cyclobutyl or cyclopentyl are optionally substituted with one to threeCl, F, OH, methyl, ethyl, propyl, C₁-C₃fluoroalkyl, C₁-C₃hydroxyalkyl,methoxy or ethoxy; or two R⁴ taken together with the respective carbonsto which each are bonded form a 4- to 6-membered heterocycloalkyl,wherein said heterocycloalkyl is optionally substituted with one tothree fluoro, C₁-C₃alkyl, C₁-C₃fluoroalkyl, —C(O)(CH₂)_(t)CN; or apharmaceutically acceptable salt thereof or a tautomer of said compoundor said salt.

In any aspect or embodiment described herein, the PTM of PTM-VIIcomprises at least one of: R¹ is methyl, ethyl, propyl or isopropylwherein each of said R¹ moieties are optionally substituted withdeuterium, fluoro or methoxy; R⁴ is independently and optionallyselected from fluoro, OH, methyl, ethyl, vinyl, propyl, wherein saidmethyl, ethyl, vinyl or propyl are optionally substituted with one, twoor three fluoro, OH or methoxy; or two R⁴ taken together with thecarbons to which they are bonded form a cyclopropyl, cyclobutyl orcyclopentyl, wherein said cyclopropyl, cyclobutyl or cyclopentyl areoptionally substituted with one to three Cl, F, OH, methyl,fluoromethyl, difluoromethyl, trifluoromethyl, ethyl, methoxymethyl,propyl, C₁-C₃haloalkyl, C₁-C₃dihaloalkyl, C₁-C₃trihaloalkyl,C₁-C₃hydroxyalkyl, methoxy, or ethoxy; R⁸ is independently hydrogen,halogen or C₁-C₆alkyl, wherein said alkyl is optionally substituted withfluoro; or a combination thereof.

In any aspect or embodiments described herein, the PTM of PTM-VII isselected from the group consisting of:5-{[(2S)-5-oxopyrrolidin-2-yl]methoxy}-3-(propan-2-yloxy)naphthalene-2-carboxamide;1-{[(2S)-4,4-difluoro-5-oxopyrrolidin-2-yl]methoxy}-7-(propan-2-yloxy)isoquinoline-6-carboxamide;1-{[(2S,4S)-4-ethyl-4-fluoro-5-oxopyrrolidin-2-yl]methoxy}-7-(propan-2-yloxy)isoquinoline-6-carboxamide;1-{[(2S,4S)-4-ethyl-5-oxopyrrolidin-2-yl]methoxy}-7-(propan-2-yloxy)isoquinoline-6-carboxamide;1-{[(2S,4S)-4-fluoro-5-oxopyrrolidin-2-yl]methoxy}-7-(propan-2-yloxy)isoquinoline-6-carboxamide;1-{[(2S)-4,4-difluoro-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide;1-{[(2S,4S)-5-oxo-4-(2,2,2-trifluoroethyl)pyrrolidin-2-yl]methoxy}-7-(propan-2-yloxy)isoquinoline-6-carboxamide;1-{[(2S,3S,4R)-4-fluoro-3-methyl-5-oxopyrrolidin-2-yl]methoxy}-7-(propan-2-yloxy)isoquinoline-6-carboxamide;3-methoxy-5-{[(2S)-5-oxopyrrolidin-2-yl]methoxy}naphthalene-2-carboxamide;1-{[(2S,4S)-4-fluoro-4-methyl-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide;1-{[(2S,3S)-4,4-difluoro-3-methyl-5-oxopyrrolidin-2-yl]methoxy}-7-(propan-2-yloxy)isoquinoline-6-carboxamide;1-{[(2S,3S,4S)-4-fluoro-3-methyl-5-oxopyrrolidin-2-yl]methoxy}-7-(propan-2-yloxy)isoquinoline-6-carboxamide;1-{[(2S,3S,4R)-4-fluoro-3-methyl-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide;1-{[(2S,3S,4S)-4-fluoro-3-methyl-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide;5-{[(2S,4S)-4-fluoro-4-methyl-5-oxopyrrolidin-2-yl]methoxy}-3-methoxynaphthalene-2-carboxamide;1-{[(2R,3R,4S)-3-ethyl-4-fluoro-3-hydroxy-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide;1-{[(2S,3S)-3-ethyl-4,4-difluoro-5-oxopyrrolidin-2-yl]methoxy}-7-(propan-2-yloxy)isoquinoline-6-carboxamide;5-{[(2S,4R)-4-fluoro-4-(hydroxymethyl)-5-oxopyrrolidin-2-yl]methoxy}-3-methoxynaphthalene-2-carboxamide;7-methoxy-1-{[(2S,3R)-3-methyl-5-oxopyrrolidin-2-yl]methoxy}isoquinoline-6-carboxamide;1-{[(2S,4S)-4-fluoro-4-(fluoromethyl)-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide;3-methoxy-5-{[(2S,3R)-3-methyl-5-oxopyrrolidin-2-yl]methoxy}naphthalene-2-carboxamide;5-{[(2S,3S,4S)-4-fluoro-3-methyl-5-oxopyrrolidin-2-yl]methoxy}-3-methoxynaphthalene-2-carboxamide;8-fluoro-5-{[(2S,3S,4S)-4-fluoro-3-methyl-5-oxopyrrolidin-2-yl]methoxy}-3-methoxynaphthalene-2-carboxamide;5-{[(2S,4R)-4-fluoro-5-oxo-4-(2,2,2-trifluoroethyl)pyrrolidin-2-yl]methoxy}-3-methoxynaphthalene-2-carboxamide;1-{[(2S,3S)-3-ethyl-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide;1-{[(2S,3R)-3-ethyl-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide;4-{[(2S,3S,4S)-4-fluoro-3-methyl-5-oxopyrrolidin-2-yl]methoxy}-6-methoxyquinoline-7-carboxamide;1-{[(2S,3S)-3-ethenyl-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide;1-{[(2S,4S)-4-fluoro-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide;1-{[(2S,4S)-4-ethyl-4-fluoro-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide;4-{[(2S,4S)-4-ethyl-4-fluoro-5-oxopyrrolidin-2-yl]methoxy}-6-methoxyquinoline-7-carboxamide;7-methoxy-1-{[(1S,2S,5R)-4-oxo-3-azabicyclo[3.1.0]hex-2-yl]methoxy}isoquinoline-6-carboxamide;4-{[(2S,4S)-4-fluoro-4-methyl-5-oxopyrrolidin-2-yl]methoxy}-6-(propan-2-yloxy)quinoline-7-carboxamide;7-methoxy-1-{[(1S,2S,5R)-6-methyl-4-oxo-3-azabicyclo[3.1.0]hex-2-yl]methoxy}isoquinoline-6-carboxamide;7-ethoxy-1-{[(2S,3S,4S)-4-fluoro-3-methyl-5-oxopyrrolidin-2-yl]methoxy}isoquinoline-6-carboxamide;7-ethoxy-1-{[(2S,4S)-4-fluoro-4-(fluoromethyl)-5-oxopyrrolidin-2-yl]methoxy}isoquinoline-6-carboxamide;7-methoxy-1-{[(1S,2S,5R)-1-methyl-4-oxo-3-azabicyclo[3.1.0]hex-2-yl]methoxy}isoquinoline-6-carboxamide;1-{[(2S,3S,4S)-3-ethyl-4-fluoro-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide;1-{[(1S,2S,5R)-1-ethyl-4-oxo-3-azabicyclo[3.1.0]hex-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide;1-{[(1R,2S,5S)-6-(fluoromethyl)-4-oxo-3-azabicyclo[3.1.0]hex-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide;1-{[(2S,3S)-3-cyclopropyl-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide;1-{[(1R,2S,5S)-5-fluoro-6-methyl-4-oxo-3-azabicyclo[3.1.0]hex-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide;7-methoxy-1-{[(2S,3R)-5-oxo-3-propylpyrrolidin-2-yl]methoxy}isoquinoline-6-carboxamide;1-{[(1S,2S,5R)-6-fluoro-4-oxo-3-azabicyclo[3.1.0]hex-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide;4-{[(2S,3S,45)-3-ethyl-4-fluoro-5-oxopyrrolidin-2-yl]methoxy}-6-methoxyquinoline-7-carboxamide;1-{[(1R,2S,5S)-5-fluoro-4-oxo-3-azabicyclo[3.1.0]hex-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide;1-{[(1R,2S,5S)-6-(difluoromethyl)-4-oxo-3-azabicyclo[3.1.0]hex-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide;1-{[(1R,2S,5S)-5-fluoro-4-oxo-3-azabicyclo[3.2.0]hept-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide;4-{[(1R,2S,5S)-5-fluoro-6-methyl-4-oxo-3-azabicyclo[3.1.0]hex-2-yl]methoxy}-6-methoxyquinoline-7-carboxamide;4-{[(1S,2S,5R)-6-fluoro-4-oxo-3-azabicyclo[3.1.0]hex-2-yl]methoxy}-6-methoxyquinoline-7-carboxamide;4-{[(1R,2S,5S)-5-fluoro-4-oxo-3-azabicyclo[3.1.0]hex-2-yl]methoxy}-6-methoxyquinoline-7-carboxamide;7-methoxy-1-{[(4S)-6-oxo-5-azaspiro[2.4]hept-4-yl]methoxy}isoquinoline-6-carboxamide;4-{[(−1R,2S,5S)-6-(fluoromethyl)-4-oxo-3-azabicyclo[3.1.0]hex-2-yl]methoxy}-6-methoxyquinoline-7-carboxamide;1-{[(2S,3S,4R)-3-ethyl-4-fluoro-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide;1-{[(2S,3S,4S)-3-ethyl-4-fluoro-5-oxopyrrolidin-2-yl]methoxy}-7-[(trideuterium)methyloxy]isoquinoline-6-carboxamide;4-{[(2S,3S,4S)-3-ethyl-4-fluoro-5-oxopyrrolidin-2-yl]methoxy}-6-methoxyquinazoline-7-carboxamide;1-{[(2S,3S,4R)-3-ethyl-4-methoxy-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide;1-{[(2S,3S,4S)-3-(pentadeuterium)ethyl-4-fluoro-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide;1-{[(2S,3S)-3-ethyl-4,4-difluoro-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide;1-{[(2S,3R,4R)-3-ethyl-4-fluoro-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide;1-{[(2S,3R)-4,4-difluoro-3-(methoxymethyl)-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide;1-{[(2S ,3R,4S)-4-fluoro-3-(methoxymethyl)-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide;7-methoxy-1-{[(2S,3S,4R)-4-methoxy-3-methyl-5-oxopyrrolidin-2-yl]methoxy}isoquinoline-6-carboxamide;1-{[(2S,3R,4R)-4-fluoro-3-(methoxymethyl)-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide;1-{[(2S,3S,4R)-3-ethyl-4-hydroxy-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide;1-{[(2S,3S)-3-(2-fluoroethyl)-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide;1-{[(2S,3S,4S)-3-ethyl-4-fluoro-5-oxopyrrolidin-2-yl]methoxy}-7-(propan-2-yloxy)isoquinoline-6-carboxamide;7-ethoxy-1-{[(2S,3S,4S)-3-ethyl-4-fluoro-5-oxopyrrolidin-2-yl]methoxy}isoquinoline-6-carboxamide;1-{[(2S,3S,4S)-3-ethyl-4-fluoro-5-oxopyrrolidin-2-yl]methoxy}-4-fluoro-7-methoxyisoquinoline-6-carboxamide;1-{[(2S,3S,4S)-3-ethyl-4-fluoro-5-oxopyrrolidin-2-yl]methoxy}-8-fluoro-7-methoxyisoquinoline-6-carboxamide;1-{[(2S,3R)-3-ethyl-5-oxopyrrolidin-2-yl]methoxy}-4-fluoro-7-methoxyisoquinoline-6-carboxamide;1-{[(2S,3R)-3-ethyl-5-oxopyrrolidin-2-yl]methoxy}-8-fluoro-7-methoxyisoquinoline-6-carboxamide;4-fluoro-7-methoxy-1-{[(1S,2S,5R)-6-methyl-4-oxo-3-azabicyclo[3.1.0]hex-2-yl]methoxy}isoquinoline-6-carboxamide;8-fluoro-7-methoxy-1-{[(1S,2S,5R)-6-methyl-4-oxo-3-azabicyclo[3.1.0]hex-2-yl]methoxy}isoquinoline-6-carboxamide;1-{[(2S,3R)-3-(fluoromethyl)-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide;1-{[(2S,3R,4S)-4-fluoro-3-(fluoromethyl)-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide;1-{[(2S,3S,4S)-3-cyclopropyl-4-fluoro-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide;1-{[(2S,3S,4R)-3-cyclopropyl-4-fluoro-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide;1-{[(2S,3S,4S)-4-fluoro-3-(2-fluoroethyl)-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide;4-(1-methyl-1H-imidazol-4-yl)-1-{[(2S)-5-oxopyrrolidin-2-yl]methoxy}-7-(propan-2-yloxy)isoquinoline-6-carboxamide;4-(1,2-dimethyl-1H-imidazol-4-yl)-1-{[(2S)-5-oxopyrrolidin-2-yl]methoxy}-7-(propan-2-yloxy)isoquinoline-6-carboxamide;4-(2-methyl-1H-imidazol-4-yl)-1-{[(2S)-5-oxopyrrolidin-2-yl]methoxy}-7-(propan-2-yloxy)isoquinoline-6-carboxamide;4-(2-methyl-1H-imidazol-4-yl)-1-{[(2S)-5-oxopyrrolidin-2-yl]methoxy}-7-(propan-2-yloxy)isoquinoline-6-carboxamide;1-{[(2S,3S,4S)-3-ethyl-4-fluoro-5-oxo(3,4-bisdeuterium)pyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide;4-{[(2S,3S,4S)-3-ethyl-4-fluoro-5-oxopyrrolidin-2-yl]methoxy}-6-methoxyquinoline-7-carboxamide;and1-{[(2S,3R,4R)-4-fluoro-3-(fluoromethyl)-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide;

In any aspect or embodiment described herein, the PTM is represented byFormula PTM-VIII (i.e., Formulas PTM-VIIIa, PTM-VIIIb, PTM-VIIIc,PTM-VIIId, PTM-VIIIe, and/or PTM-VIIIf, which correspond to Formulas I,II, III, IV, VI, and VIII, respectively, from U.S. Patent ApplicationPublication No. 2016/0002265 A1, which is incorporated herein in itsentirety for all purposes):

wherein:

-   -   Ring A of PTM-VIII is phenylene or 5- to 6-membered        heteroarylene containing 1-3 heteroatoms chosen from O, S, and        N, wherein ring A is optionally substituted with lower alkyl        that is further optionally substituted;    -   Ring B of PTM-VIII is phenylene, 5- to 6-membered        heterocycloalkylene containing 1-3 heteroatoms chosen from O, S,        and N, or 5- to 6-membered heteroarylene containing 1-3        heteroatoms chosen from O, S, and N, wherein ring B is        optionally substituted with lower alkyl or lower alkyloxyalkyl,        either of which is further optionally substituted;    -   R² of PTM-VIII is chosen from hydrogen and lower alkyl;    -   R³ of PTM-VIII is chosen from hydrogen, lower alkyl optionally        substituted with alkoxy, amino, N-(alkyl)amino,        N,N-(dialkyl)amino, or phenyl, heterocycloalkyl, and heteroaryl,        wherein phenyl, heterocycloalkyl, and heteroaryl are optionally        substituted with one or two groups independently chosen from        lower alkyl and wherein alkoxy is optionally substituted with        tri(alkyl)silyl;    -   R⁴ of PTM-VIII is chosen from heteroarylene and arylene, each of        which is optionally substituted, or R⁴ and R³ taken together        with the nitrogen to which they are bound, form an optionally        substituted 3- to 7-membered heterocycloalkyl ring, or R⁴ is an        alkylene chain having 1-3 carbon atoms that is optionally        substituted with one or two groups independently chosen from        lower alkyl and cycloalkyl, each of which groups is optionally        substituted with hydroxyl or alkoxy, or R⁴ is absent;    -   R⁵ of PTM-VIII is chosen from C(O)NR⁵¹, NR⁵², and O, or R⁵ is        absent, provided that if R⁴ is absent, then R⁵ is absent;    -   R⁶ of PTM-VIII is an alkylene or alkenylene chain having one or        two double bonds, wherein the alkylene or alkenylene chain has 2        to 10 carbon atoms, the alkylene or alkenylene chain is        optionally substituted with one or two groups independently        chosen from lower alkyl, cycloalkyl and phenyl, each of which        groups is optionally substituted with hydroxyl, alkoxy,        —C(O)OR⁸⁵, —C(O)NR⁸²R⁸³, benzoyl, and benzyl, further wherein        one or two of the carbon atoms in the alkylene or alkenylene        chain is optionally replaced by an O, S, SO, SO₂, C(O)NR⁵¹, or        NR⁶¹, and wherein one of the carbon atoms in the alkylene or        alkenylene chain, is optionally connected by the nitrogen atom        of C(O)NR⁵¹ or NR⁶¹ to form a 5- to 7-membered ring, which may        further be substituted with oxo, wherein two of the carbon atoms        in the alkylene or alkenylene chain, are optionally connected by        a two or three carbon atom alkylene or alkenylene chain to form        a 5- to 7-membered ring;    -   R⁷ of PTM-VIII is chosen from NR⁷¹ and O, or R⁷ is absent;    -   R²¹ of PTM-VIII is chosen from hydrogen and lower alkyl        optionally substituted with lower alkoxy, wherein lower alkoxy        is optionally substituted with tri(alkyl)silyl;    -   R⁴¹ of PTM-VIII is independently chosen from heterocycloalkyl,        lower alkyl optionally substituted with —C(O)OR⁹, amino,        N-(alkyl)amino, N,N-(dialkyl)amino, cycloalkyl, or        heterocycloalkyl, —C(O)OR⁹, hydroxyl, and —C(O)NR¹⁰R¹¹, wherein        R⁹ is chosen from hydrogen and lower alkyl, R¹⁰ and R¹¹ are        independently hydrogen and lower alkyl, or R¹⁰ and R¹¹, together        with the nitrogen to which they are bound form a        heterocycloalkyl, and each lower alkyl, cycloalkyl and        heterocycloalkyl is optionally substituted with one, two, or        three groups independently chosen from —C(O)OR⁹, lower alkyl,        lower alkoxy, hydroxyl, halogen, amino, N-(alkyl)amino,        N,N-(dialkyl)amino, and heterocycloalkyl;    -   R⁵¹ of PTM-VIII is chosen from hydrogen and lower alkyl;    -   R⁵² of PTM-VIII is chosen from hydrogen, lower alkyl, and        —C(O)OR^(s1);    -   R⁶¹ of PTM-VIII is chosen from hydrogen, lower alkyl,        —(CH₂)_(n)C(O)OR⁸¹, —(CH₂)_(n)C(O)NR⁸²R⁸³, —C(O)R⁸⁴,        —C(O)(CH₂)_(p)NR⁸²C(O)OR⁸¹, —C(O)(CH₂)_(p)NR⁸²R⁸³;    -   R⁷¹ of PTM-VIII is chosen from hydrogen, lower alkyl, and        —C(O)OR⁸¹;    -   R⁸¹ of PTM-VIII is hydrogen or lower alkyl;    -   R⁸² of PTM-VIII is hydrogen or lower alkyl,    -   R⁸³ of PTM-VIII is hydrogen or lower alkyl,    -   R⁸⁴ of PTM-VIII is hydrogen, lower alkyl, C₃-C₆cycloalkyl or        tetrahydropyran, wherein the lower alkyl is optionally        substituted with hydroxy or —C(O)OR⁸¹;    -   R⁸⁵ of PTM-VIII is hydrogen, lower alkyl, or benzyl,    -   n of PTM-VIII is 0, 1, 2, or 3;    -   p of PTM-VIII is 1 or 2;    -   Z of PTM-VIII is chosen from O, S, and NR²¹; and    -   the PTM-VIII is covalently joined to a ULM, a chemical linker        group (L), a CLM, an ILM, a VLM, MLM, a ULM′, a CLM′, a ILM′, a        VLM′, a MLM′, or combination thereof.

In any aspect or embodiment described herein, the PTM-I is covalentlyjoined to a ULM, a chemical linker group (L), a CLM, an ILM, a VLM, MLM,a ULM′, a CLM′, a ILM′, a VLM′, a MLM′, or combination thereof via an Rgroup (e.g., R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R²¹, R⁴¹,R⁵¹, R⁵², R⁶¹, R⁷¹, R⁸¹, R⁸², R⁸³, R⁸⁴, or R⁸⁵).

In any aspect or embodiment described herein, the Ring A of PTM-VIII isselected from the group consisting of:

wherein R¹ is hydrogen or lower alkyl, X is O, S, or NR¹¹, and R¹¹ ishydrogen or lower alkyl, and Y is C, CH, or N.

In any aspect or embodiment described herein, the Ring B of PTM-VIII isselected from the group consisting of:

wherein: X¹, Y¹, and Z¹ are independently chosen from NR²¹, O, C(R²¹)₂,and S; X², Y², and Z² are independently chosen from N and CR²¹; and R²is chosen from hydrogen and lower alkyl, wherein for each occurrence,R²¹ is independently chosen from hydrogen and lower alkyl optionallysubstituted with lower alkoxy, wherein lower alkoxy is optionallysubstituted with tri(alkyl)silyl.

In any aspect or embodiment described herein, the Ring B of PTM-VIII is

wherein: Z is chosen from O, S, and NR²¹; and R² is chosen from hydrogenand lower alkyl, if present, R²¹ is chosen from hydrogen and lower alkyloptionally substituted with lower alkoxy, wherein lower alkoxy isoptionally substituted with tri(alkyl)silyl.

In any aspect or embodiment described herein, the R⁴ of PTM-VIII isarylene optionally substituted with one or more R⁴² wherein for eachoccurrence, R⁴² is independently chosen from: heterocycloalkyl; loweralkyl optionally substituted with —C(O)OR⁹, amino, N-(alkyl)amino,N,N-(dialkyl)amino, cycloalkyl, or heterocycloalkyl; —C(O)OR⁹; hydroxyl;and —C(O)NR¹⁰R¹¹, wherein R⁹ is chosen from hydrogen and lower alkyl,R¹⁰ and R¹¹ are independently hydrogen and lower alkyl, or R⁹ and R¹⁰,together with the nitrogen to which they are bound form aheterocycloalkyl, and each lower alkyl, cycloalkyl and heterocycloalkylis optionally substituted with one, two, or three groups independentlychosen from —C(O)OR⁹, lower alkyl, lower alkoxy, hydroxyl, halogen,amino, N-(alkyl)amino, N,N-(dialkyl)amino, and heterocycloalkyl.

In any aspect or embodiment described herein, the R⁴ of the PTM-VIII isselected from the group consisting of

wherein.

In any aspect or embodiment described herein, the R⁴ of PTM-VIII isheteroarylene optionally substituted with one or more R⁴¹.

In any aspect or embodiment described herein, the R⁴¹ of PTM-VIII isheterocycloalkyl chosen from tetrahydropyranyl, piperidinyl,hexahydropyrimidinyl, and morpholinyl, each of which is optionallysubstituted with one, two, or three groups independently chosen from—C(O)OR⁹, lower alkyl, lower alkoxy, hydroxyl, halogen, amino,N-(alkyl)amino, N,N-(dialkyl)amino, and heterocycloalkyl.

In any aspect or embodiment described herein, R³ and R⁴ of PTM-VIIItaken together with the nitrogen to which they are bound, form a 3- to7-membered heterocycloalkyl ring optionally substituted with one or moreR⁴⁴ wherein for each occurrence, R⁴⁴ is independently chosen from:heterocycloalkyl; lower alkyl optionally substituted with —C(O)OR⁹,amino, N-(alkyl)amino, N,N-(dialkyl)amino, cycloalkyl, orheterocycloalkyl; —C(O)OR⁹; hydroxyl; and —C(O)NR¹⁰R¹¹, wherein R⁹ ischosen from hydrogen and lower alkyl, R¹⁰ and R¹¹ are independentlyhydrogen and lower alkyl, or R⁹ and R¹⁰, together with the nitrogen towhich they are bound form a heterocycloalkyl, and each lower alkyl,cycloalkyl and heterocycloalkyl is optionally substituted with one, two,or three groups independently chosen from —C(O)OR⁹, lower alkyl, loweralkoxy, hydroxyl, halogen, amino, N-(alkyl)amino, N,N-(dialkyl)amino,and heterocycloalkyl.

In any aspect or embodiment described herein, R³ and R⁴ of PTM-VIIItaken together with the nitrogen to which they are bound, for a 3- to7-membered hereocycloalkyl ring of

In any aspect or embodiment described herein, R⁴ of PTM-VII is absent.

In any aspect or embodiment described herein, the PTM is represented byFormula PTM-IX (i.e., Formulas PTM-IXa, PTM-IXb, PTM-IXc, PTM-IXd,and/or PTM-IXe, which correspond to Formulas I, II, III, IV, and thestructure produced on page 20, respectively, from International PatentApplication Publication WO 2016/011390 A1, which is incorporated hereinin its entirety for all purposes, PTM-IXf, PTM-IXg, PTM-IXh, PTM-IXi,PTM-IXj, PTM-IXk, PTM-IXl, and/or PTM-IXm):

wherein:

-   -   Ring A of PTM-IX is selected from phenyl and 5- or 6-membered        heteroaryl;    -   Ring B of PTM-IX is selected from phenyl and 5- or 6-membered        heteroaryl;    -   Ring C of PTM-IX is selected from a 5- or 6-membered cycloalkyl        or cycloheteroalkyl;    -   Ring D of PTM-IX selected from phenyl, 5-membered aryl or        heteroaryl, 6-member aryl or heteroaryl, 5-membered cycloalkyl        or cycloheteroalkyl, or 6-membered cycloalkyl or        cycloheteroalkyl;    -   n of PTM-IX is 0, 1, or 2;    -   p of PTM-IX is 0, 1, or 2;    -   one of W and X of PTM-IX is N, and the other of W and X is C;    -   Y of PTM-IX is N or C—R²;    -   R¹ of PTM-IX is selected from C₁₋₆alkyl, C₂₋₆alkenyl,        C₂₋₆alkynyl, C₃₋₆cycloalkyl, 3-to 6-membered saturated        heterocyclyl, halo, —CN, —C(R^(1a))═NR(OR^(1a)),        —C(R^(1a))═N(R^(1a)), —C(O)R^(1a)C(O)₂R^(1a), —C(O)N(R^(1a))₂,        —NO₂, —N(R^(1a))₂, —N(R^(1a))C(O)R^(1a), —N(R^(1a))C(O)₂R^(1a),        N(R^(1a))C(O)N(R^(1a))₂, —N(R^(1a))S(O)₂R^(1a), —OR^(1a),        —OC(O)R^(1a), —OC(O)N(R^(1a))₂, —SR^(1a), —S(O)R^(1a),        S(O)₂R^(1a), —S(O)N(R^(1a))₂, and —S(O)₂N(R^(1a))₂, wherein said        C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl, and 3-to        6-membered saturated heterocyclyl are optionally substituted        with one or more R¹⁰; or two R¹ substituents, together with        their intervening atoms, form a C₅₋₇cycloalkyl or a saturated 5-        to 7-membered heterocyclic ring, wherein said C₅₋₇cycloalkyl or        a saturated 5- to 7-membered heterocyclic ring are optionally        substituted with one or more R¹⁵;    -   R^(1a) of PTM-IX in each occurrence is independently selected        from H, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, 3- to 6-membered        monocyclic carbocyclyl, and 3- to 6-membered monocyclic        heterocyclyl wherein said C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,        3- to 6-membered monocyclic carbocyclyl, and 3- to 6-membered        monocyclic heterocyclyl in each occurrence are optionally and        independently substituted with one or more R¹⁰;    -   R¹⁰ of PTM-IX in each occurrence is independently selected from        ĈaUcyl, C₂₋₆alkenyl, C₂-6alkynyl, 3- to 6-membered carbocyclyl,        3-to 6-membered heterocyclyl, halo, —CN,        C(R^(10a))═NR(OR^(10a)), —C(R^(10a))═N(R^(10a)), —C(O)R^(10a),        —C(O)₂R^(10a), —C(O)N(R^(10a))₂, —NO₂, —N(R^(10a))₂,        —N(R^(10a))C(O)R^(10a), —N(R^(10a))C(O)₂R^(10a),        —N(R^(10a))C(O)N(R^(10a))₂, —N(R^(10a))S(O)₂R^(10a), —OR^(10a),        —OC(O)R^(10a), —OC(O)N(R^(10a))₂, —SR^(10a), —S(O)R^(10a),        —S(O)₂R^(10a), —S(O)N(R^(10a))₂, and —S(O)₂N(R^(10a))    -   R^(10a) of PTM-IX in each occurrence is independently selected        from H and C₁₋₆alkyl, wherein said C₁₋₆alkyl is optionally        substituted with one or more halo;    -   R¹⁵ of PTM-IX in each occurrence is independently selected from        C₁₋₆alkyl, C₂₋₆alkenyl, C₂-6alkynyl, 3- to 6-membered        carbocyclyl, 3-to 6-membered heterocyclyl, halo, —CN,        —C(R^(15a))═NR(OR^(15a)), —C(R^(15a))═N(R^(15a)), —C(O)R^(15a),        —C(O)₂R^(15a), —C(O)N(R^(15a))₂, —NO₂, —N(R^(15a))₂,        —N(R^(15a))C(O)R^(15a), —N(R^(15a))C(O)₂R^(15a),        —N(R^(15a))C(O)N(R^(15a))₂, —N(R^(15a))S(O)₂R^(15a), —OR^(15a),        —OC(O)R^(15a), —OC(O)N(R^(15a))₂, —SR^(15a), —S(O)R^(15a),        —S(O)₂R^(15a), —S(O)N(R^(15a))₂, and —S(O)₂N(R^(15a))₂;    -   R^(15a) of PTM-IX in each occurrence is independently selected        from H and C₁₋₆alkyl, wherein said C₁₋₆alkyl is optionally        substituted with one or more halo;    -   R² of PTM-IX is selected from H, C₁₋₆alkyl, C₂₋₆alkenyl,        C₂₋₆alkynyl, 3- to 7-membered carbocyclyl, 3-to 7-membered        heterocyclyl, halo, —CN, —C(R^(2a))═NR(OR^(2a)),        C(R^(2a))═N(R^(2a)), —C(O)R^(2a), —C(O)₂R^(2a), —C(O)N(R^(2a))₂,        —NO₂, —N(R^(2a))₂, —N(R^(2a))C(O)R^(2a), —N(R^(2a))C(O)₂R^(2a),        —N(R^(2a))C(O)N(R^(2a))₂, —N(R^(2a))S(O)₂R^(2a), —OR^(2a),        —OC(O)R^(2a), OC(O)N(R^(2a))₂, —SR^(2a), —S(O)R^(2a),        —S(O)₂R^(2a), —S(O)N(R^(2a))₂, and —S(O)₂N(R^(2a))₂, wherein        said C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, 3-to 7-membered        carbocyclyl, and 3-7 membered heterocyclyl are optionally        substituted with one or more R²⁰;    -   R^(2a) of PTM-IX in each occurrence is independently selected        from H and C₁₋₆alkyl, wherein said C₁₋₆alkyl in each occurrence        is optionally and independently substituted with one or more        R²⁰;    -   R²⁰ of PTM-IX in each occurrence is independently selected from        C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₇cycloalkyl, 3-to        7-membered saturated heterocyclyl, halo, —CN,        —C(R^(20a))═NR(OR^(20a)), —C(R^(20a))═N(R^(20a)), —C(O)R^(20a),        —C(O)₂R^(20a), —C(O)N(R^(20a))₂, —NO₂, —N(R^(20a))₂,        —N(R^(20a))C(O)R^(20a), —N(R^(20a))C(O)₂R^(20a),        —N(R^(20a))C(O)N(R^(20a))₂, —N(R^(20a))S(O)₂R^(20a), —OR^(20a),        —OC(O)R^(20a), —OC(O)N(R^(20a))₂, —SR^(20a), —S(O)R^(20a),        —S(O)₂R^(20a), —S(O)N(R^(20a))₂, and —S(O)₂N(R )₂, wherein said        C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₇cycloalkyl, and 3-7        membered saturated heterocyclyl in each occurrence are        optionally and independently substituted with one or more R²⁵;    -   R^(20a) of PTM-IX in each occurrence is independently selected        from H and C₁₋₆alkyl, wherein said C₁₋₆alkyl is optionally        substituted with R²⁵;    -   R²⁵ of PTM-IX is selected from halo and —OR^(25a);    -   R^(25a) of PTM-IX is selected from H and C₁₋₆alkyl;    -   R³ of PTM-IX is selected from C₁₋₆alkyl, C₂₋₆alkenyl,        C₂₋₆alkynyl, C₃₋₆cycloalkyl, 3-to 6-membered saturated        heterocyclyl, halo, —CN, —C(R^(3a))═NR(OR^(3a)),        —C(R^(3a))═N(R^(3a)), C(O)R^(3a), —C(O)₂R^(3a), —C(O)N(R^(3a))₂,        —NO₂, —N(R^(3a))₂, —N(R^(3a))C(O)R^(3a), —N(R^(3a))C(O)₂R^(3a),        N(R^(3a))C(O)N(R^(3a))₂, —N(R^(3a))S(O)₂R^(3a), —OR^(3a),        —OC(O)R^(3a), —OC(O)N(R^(3a))₂, —SR^(3a), —S(O)R^(3a),        S(O)₂R^(3a), —S(O)N(R^(3a))₂, and —S(O)₂N(R^(3a))₂, wherein said        C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₆cycloalkyl, and 3-to        6-membered saturated heterocyclyl are optionally substituted        with one or more R³⁰;    -   R^(3a) of PTM-IX in each occurrence is independently selected        from H, C₁₋₆alkyl, 3- to 6-membered carbocyclyl, and 3- to        6-membered heterocyclyl, wherein said C₁₋₆alkyl, 3- to        6-membered carbocyclyl, and 3- to 6-membered heterocyclyl in        each occurrence are optionally and independently substituted        with one or more R³⁰;    -   R³⁰ of PTM-IX in each occurrence is independently selected from        C₁₋₆alkyl, C₂₋₆alkenyl, C₂-6alkynyl, 3- to 6-membered        carbocyclyl, 3-to 6-membered heterocyclyl, halo, —CN,        —C(R^(30a))═NR(OR^(30a)), —C(R^(30a))═N(R^(30a)), —C(O)R^(30a),        —C(O)₂R^(30a), —C(O)N(R^(30a))₂, —NO₂, —N(R^(30a))₂,        —N(R^(30a))C(O)R^(30a), —N(R^(30a))C(O)₂R^(30a),        —N(R^(30a))C(O)N(R^(30a))₂, —N(R^(30a))S(O)₂R^(30a), — OR^(30a),        —OC(O)R^(30a), —OC(O)N(R^(30a))₂, —SR^(30a), —S(O)R^(30a),        —S(O)₂R^(30a), —S(O)N(R^(30a))₂, and —S(O)₂N(R^(30a))₂, wherein        said C₁₋₃alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, 3-6 membered        carboyclyl, 3- to 6-membered heterocyclyl in each occurence are        optionally and independently substituted with one or more R³⁵;    -   R^(30a) of PTM-IX in each occurrence is independently selected        from H and C₁₋₆alkyl, wherein said C₁₋₆alkyl is optionally        substituted with one or more R³⁵;    -   R³⁵ of PTM-IX in each occurrence is independently selected from        halo and —OR^(35a);    -   R^(35a) of PTM-IX in each occurrence is independently selected        from H and C₁₋₆alkyl;    -   R^(35b) of PTM-IX in each occurrence is independently selected        from H, halo, optionally substituted alkoxy (e.g., optionally        substituted C₁-C₄ alkoxy), optionally substituted alkyl (e.g.,        C₁-C₄ alkyl optionally substituted with halo or hydroxy),        hydroxyalkyl (e.g. C₁-C₄ hydroxyalkyl), or haloalkyl (e.g.,        C₁-C₄ haloalkyl);    -   R^(35c) of PTM-IX in each occurrence is independently selected        from halo or haloalkyl (e.g., C₁-C₄ haloalkyl);    -   R⁴ of PTM-IX is selected from H, halo, C₁₋₆alkyl, N(R^(4a))₂,        and —OR^(4a);    -   R^(4a) of PTM-IX in each occurrence is independently selected        from H and C₁₋₆alkyl; and    -   the PTM-IX is covalently joined to a ULM, a chemical linker        group (L), a CLM, an ILM, a VLM, MLM, a ULM′, a CLM′, a ILM′, a        VLM′, a MLM′, or combination thereof.

In any aspect or embodiment described herein, the PTM-IX is covalentlyjoined to a ULM, a chemical linker group (L), a CLM, an ILM, a VLM, MLM,a ULM′, a CLM′, a ILM′, a VLM′, a MLM′, or combination thereof via an Rgroup (e.g., R¹, R^(1a), R², R^(2a), R³, R^(3a), R⁴, R^(4a), R¹⁰,R^(10a), R¹⁵, R^(15a), R²⁰, R^(20a), R²⁵, R^(25a), R³⁰, R^(30a), R³⁵,R^(35a), R^(35b), or R^(35c)).

In any aspect or embodiment described herein, the PTM of PTM-IXcomprises R¹ is selected from C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₃₋₆cycloalkyl, 3-to 6-membered saturated heterocyclyl, halo, —CN,—C(R^(1a))═NR(OR^(1a)), —C(R^(1a))═N(R^(1a)), —C(O)R^(1a), —C(O)₂R^(1a),—C(O)N(R^(1a))₂, —N(R^(1a))₂, —N(R^(1a))C(O)R^(1a),—N(R^(1a))C(o)₂R^(1a), —N(R^(1a))C(O)N(R^(1a))₂, —N(R^(1a))S(O)₂R^(1a),—OR^(1a), —OC(O)R^(1a), —OC(O)N(R^(1a))₂, —SR^(1a), —S(O)R^(1a),—S(O)₂R^(1a), —S(O)N(R^(1a))₂, and —S(O)₂N(R^(1a))₂, wherein saidC₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl, and 3-to 6-memberedsaturated heterocyclyl are optionally substituted with one or more R¹⁰;or two R¹ substituents, together with their intervening atoms, form aC₅₋₇cycloalkyl or a saturated 5- to 7-membered heterocyclic ring,wherein said C₅₋₇cycloalkyl or a saturated 5- to 7-membered heterocyclicring are optionally substituted with one or more R¹⁵.

In any aspect or embodiment described herein, wherein: Ring A of PTM-IXis 5- or 6-membered heteroaryl and Ring B of PTM-IX is 5- or 6-memberedheteroaryl; Ring A of PTM-IX is a 5- or 6-membered heteroaryl and theRing B of PTM-IX is phenyl; Ring A of PTM-IX is a phenyl and Ring B ofPTM-IX is a 5- or 6-membered heteroaryl; and Ring A is a phenyl and RingB is phenyl, wherein the 5- or 6-membered heteroaryl in each occurrencemay be independently selected from pyrrolyl, furanyl, thiophenyl (orthienyl), imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl,isothiazolyl, furazanyl, oxadiazolyl, thiadiazolyl, dithiazolyl,triazolyl, tetrazolyl, pyridinyl, pyranyl, thiopyranyl, pyrazinyl,pyrimidinyl, pyridazinyl, oxazinyl, thiazinyl, dioxinyl, dithiinyl,oxathianyl, triazinyl, or tetrazinyl.

In any aspect or embodiment described herein, the PTM of PTM-IX isselected from the group consisting of:6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-amine;2-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyrimidin-4-amine;2-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-4-amine;(6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)methanamine;(2-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-4-yl)methanamine;4-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-amine;5-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-3-amine;3-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)aniline;(2-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyrimidin-4-yl)methanamine;4-methyl-5-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-3-amine;3-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)-5-nitropyridin-2-ol;3-amino-5-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-4-ol;N-methyl-5-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-3-amine;N,N-dimethyl-1-(6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)methanamine;5-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)-1,2,3,4-tetrahydroisoquinoline;2-methyl-5-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)-1,2,3,4-tetrahydroisoquinoline;6-(2-methylisoindolin-4-yl)-1-(6-methylpyridin-2-yl)-1H-indazole;N-methyl-1-(3-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)phenyl)methanamine;3-(6-(3-aminophenyl)-1H-indazol-1-yl)benzonitrile;3-(1-(pyridin-2-yl)-1H-indazol-6-yl)aniline;6-(6-(3-aminophenyl)-1H-indazol-1-yl)picolinonitrile;3-(1-(4,6-dimethylpyridin-2-yl)-1H-indazol-6-yl)aniline;3-(1-(5,6-dimethylpyridin-2-yl)-1H-indazol-6-yl)aniline;3-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)aniline;5-(1-(6-cyclopropylpyridin-2-yl)-1H-indazol-6-yl)pyridin-3-amine;5-(1-(6-cyclobutylpyridin-2-yl)-1H-indazol-6-yl)pyridin-3-amine;6-(6-(5-aminopyridin-3-yl)-1H-indazol-1-yl)picolinonitrile;6-(6-(5-aminopyridin-3-yl)-1H-indazol-1-yl)picolinic acid;6-(6-(5-aminopyridin-3-yl)-1H-indazol-1-yl)picolinamide;6-(6-(5-aminopyridin-3-yl)-1H-indazol-1-yl)-N-methylpicolinamide;3-(6-(5-aminopyridin-3-yl)-1H-indazol-1-yl)benzonitrile;2-(6-(5-aminopyridin-3-yl)-1H-indazol-1-yl)-6-methylisonicotinonitrile;2-(6-(5-aminopyridin-3-yl)-1H-indazol-1-yl)isonicotinonitrile;5-(1-(4-methylpyrimidin-2-yl)-1H-indazol-6-yl)pyridin-3-amine;2-(6-(5-aminopyridin-3-yl)-1H-indazol-1-yl)pyrimidine-4-carbonitrile;5-(1-(3-chloro-6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-3-amine;5-(1-(4-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-3-amine;5-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-3-amine;5-(3-(6-methylpyridin-2-yl)imidazo[1,5-a]pyridin-6-yl)pyridin-3-amine;3-(3-(6-methylpyridin-2-yl)imidazo[1,5-a]pyridin-6-yl)aniline;5-(5-fluoro-1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-3-amine;5-(5-methyl-1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-3-amine;6-(6-(6-(aminomethyl)pyridin-2-yl)-1H-indazol-1-yl)picolinonitrile;6-(6-(6-(aminomethyl)pyridin-2-yl)-1H-indazol-1-yl)picolinamide;(6-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)methanamine;methyl6-(5-aminopyridin-3-yl)-1-(6-cyanopyridin-2-yl)-1H-indazole-4-carboxylate;methyl6-(5-aminopyridin-3-yl)-1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazole-4-carboxylate;6-(5-aminopyridin-3-yl)-1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazole-4-carboxylicacid;6-(5-aminopyridin-3-yl)-1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazole-4-carboxamide;5-(4-(aminomethyl)-1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-3-amine;(6-(5-aminopyridin-3-yl)-1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-4-yl)methanol;1-(6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine;methyl6-(6-(1-aminoethyl)pyridin-2-yl)-1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazole-4-carboxylate;(6-(6-(1-aminoethyl)pyridin-2-yl)-1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-4-yl)methanol;6-(6-(1-aminoethyl)pyridin-2-yl)-N,N-dimethyl-1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazole-4-carboxamide;6-(6-(1-aminoethyl)pyridin-2-yl)-N-methyl-1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazole-4-carboxamide;6-(5-aminopyridin-3-yl)-N,N-dimethyl-1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazole-4-carboxamide;6-(5-aminopyridin-3-yl)-N-methyl-1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazole-4-carboxamide;2-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-7-amine ;2-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)-5,6,7,8-tetrahydroquinolin-8-amine;6-(6-(5-aminopyridin-3-yl)-1H-indazol-1-yl)-N,N-dimethylpicolinamide;6-(6-(5-aminopyridin-3-yl)-1H-indazol-1-yl)-N-(2-hydroxyethyl)picolinamide;6-(6-(5-aminopyridin-3-yl)-1H-indazol-1-yl)-N-(3-hydroxypropyl)picolinamide;6-(6-(5-aminopyridin-3-yl)-1H-indazol-1-yl)-N-(2-hydroxypropyl)picolinamide;(6-(6-(5-aminopyridin-3-yl)-1H-indazol-1-yl)pyridin-2-yl)(3-hydroxyazetidin-1-yl)methanone;6-(6-(5-aminopyridin-3-yl)-1H-indazol-1-yl)-N-(2-(dimethylamino)ethyl)picolinamide;6-(6-(5-aminopyridin-3-yl)-1H-indazol-1-yl)-N-(2-cyanoethyl)picolinamide;6-(6-(5-aminopyridin-3-yl)-1H-indazol-1-yl)-N-(3-cyanopropyl)picolinamide;N-(2-aminoethyl)-6-(6-(5-aminopyridin-3-yl)-1H-indazol-1-yl)picolinamide;6-(6-(5-aminopyridin-3-yl)-1H-indazol-1-yl)-N-(cyanomethyl)picolinamide;6-(6-(5-aminopyridin-3-yl)-1H-indazol-1-yl)-N-(2-(methylsulfonyl)ethyl)picolinamide;3-(6-(5-aminopyridin-3-yl)imidazo[1,5-a]pyridin-3-yl)benzonitrile;6-(6-(5-aminopyridin-3-yl)imidazo[1,5-a]pyridin-3-yl)picolinonitrile;6-(6-(5-aminopyridin-3-yl)imidazo[1,5-a]pyridin-3-yl)picolinamide;5-(3-(6-(trifluoromethyl)pyridin-2-yl)imidazo[1,5-a]pyridin-6-yl)pyridin-3-amine;1-(6-(3-(6-(trifluoromethyl)pyridin-2-yl)imidazo[1,5-a]pyridin-6-yl)pyridin-2-yl)ethanamine;2-(aminomethyl)-6-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-4-amine;2-(6-(6-(5-aminopyridin-3-yl)-1H-indazol-1-yl)pyridin-2-yl)acetonitrile;2-(6-(6-(5-aminopyridin-3-yl)-1H-indazol-1-yl)pyridin-2-yl)acetic acid;1-(6-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine;3-amino-5-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)benzoicacid;3-amino-N-(cyanomethyl)-5-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)benzamide;6-amino-N-(cyanomethyl)-4-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)picolinamide;3-amino-N-(2-aminoethyl)-5-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)benzamide;1-(3-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)phenyl)ethanamine;1-(5-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-3-yl)ethanamine;1-(4-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine;6-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyrazine-2-carbonitrile;(6-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyrazin-2-yl)methanamine;4-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyrimidine-2-carbonitrile;(4-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyrimidin-2-yl)methanamine;6-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyrazin-2-amine;6-(6-(pyrrolidin-2-yl)pyridin-2-yl)-1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazole;6-(6-(1-methylpyrrolidin-2-yl)pyridin-2-yl)-1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazole;1-(6-(3-(6-methylpyridin-2-yl)imidazo[1,5-a]pyridin-6-yl)pyridin-2-yl)ethanamine;6-(6-(1-aminoethyl)pyridin-2-yl)-1-(6-methylpyridin-2-yl)-1H-indazol-4-amine;6-(6-(1-aminoethyl)pyridin-2-yl)-N-methyl-1-(6-methylpyridin-2-yl)-1H-indazol-4-amine;6-(6-(1-aminoethyl)pyridin-2-yl)-N,N-dimethyl-1-(6-methylpyridin-2-yl)-1H-indazol-4-amine;N-(6-(6-(1-aminoethyl)pyridin-2-yl)-1-(6-methylpyridin-2-yl)-1H-indazol-4-yl)acetamide;1-(6-(4-(aminomethyl)-1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine;N-((6-(6-(1-aminoethyl)pyridin-2-yl)-1-(6-methylpyridin-2-yl)-1H-indazol-4-yl)methyl)acetamide;1-(6-(4-chloro-1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine;1-(6-(4-cyclopropyl-1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine;1-(6-(1-(6-methylpyridin-2-yl)-4-(prop-1-en-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine;1-(6-(4-ethyl-1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine;1-(6-(4-isopropyl-1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine;1-(6-(1-(6-methylpyridin-2-yl)-4-(trifluoromethyl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine;methyl6-(6-(1-aminoethyl)pyridin-2-yl)-1-(6-methylpyridin-2-yl)-1H-indazole-4-carboxylate;6-(6-(1-aminoethyl)pyridin-2-yl)-1-(6-methylpyridin-2-yl)-1H-indazole-4-carboxylicacid;6-(6-(1-aminoethyl)pyridin-2-yl)-1-(6-methylpyridin-2-yl)-1H-indazol-4-yl)methanol;6-(6-(1-aminoethyl)pyridin-2-yl)-N-methyl-1-(6-methylpyridin-2-yl)-1H-indazole-4-carboxamide;N-methyl-1-(6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine;N-methyl-1-(6-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine;1-(6-(1-(6-cyclopropylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine;1-(6-(1-(6-ethylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine;1-(6-(1-(6-isopropylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine;1-(6-(1-(pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine;(6-(6-(6-(1-aminoethyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol;1-(4-methyl-6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine;1-(6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)-4-(trifluoromethyl)pyridin-2-yl)ethanamine;6-(6-(6-(1-aminoethyl)pyridin-2-yl)-1H-indazol-1-yl)picolinamide;1-(6-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)propan-1-amine;cyclopropyl(6-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)methanamine;2-(6-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)propan-2-amine;1-(6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanol;cyclopropyl(6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)methanamine;1-(6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)butan-1-amine;1-(6-(1-(4-methylthiazol-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine;1-(6-(1-(5-methylthiazol-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine;1-(6-(1-(2-methylthiazol-4-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine;1-(6-(1-(1-methyl-1H-pyrazol-3-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine;1-(6-(1-(1-methyl-1H-imidazol-4-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine;(2-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)thiazol-4-yl)methanamine;(2-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)thiazol-5-yl)methanamine;(R)-1-(6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine;(S)-1-(6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine;(S)-(6-(6-(6-(1-aminoethyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol;(R)-(6-(6-(6-(1-aminoethyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol;(S)-(6-(6-(6-(1-aminobutyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol;(R)-(6-(6-(6-(1-aminobutyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol;1-(6-methylpyridin-2-yl)-1H-pyrazolo[4,3-c]pyridin-7-amine;2-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)isonicotinamide;N,N-dimethyl-5-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-3-amine;1-(6-methylpyridin-2-yl)-6-(5-(pyrrolidin-1-yl)pyridin-3-yl)-1H-indazole;6-methyl-5-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-3-amine;5-(1-(6-cyclopentylpyridin-2-yl)-1H-indazol-6-yl)pyridin-3-amine;5-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)-3,4-dihydroisoquinolin-1(2H)-one;1-(6-(4-fluoro-1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanone;N-(5-(4-cyano-1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-3-yl)-2,2,2-trifluoroacetamide;1-(6-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine;2-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)-5H-cyclopenta[b]pyridin-7(6H)-one;6-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)picolinonitrile;2-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)-6,7-dihydroquinolin-8(5H)-one;6-amino-4-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)picolinicacid;6-(6-(1-aminoethyl)pyridin-2-yl)-1-(6-methylpyridin-2-yl)-1H-indazole-4-carbonitrile;1-(6-(4-(aminomethyl)-2-(6-methylpyridin-2-yl)-2H-indazol-6-yl)pyridin-2-yl)ethanamine;N,N-dimethyl-1-(6-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine;N-((6-(6-(1-aminoethyl)pyridin-2-yl)-2-(6-methylpyridin-2-yl)-2H-indazol-4-yl)methyl)acetamide;1-(6-(4-chloro-1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanone;(Z)-1-(6-(4-chloro-1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanoneoxime;N,N-dimethyl-1-(6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine;N,N-dimethyl-1-(6-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine;1-(6-(3-(6-(trifluoromethyl)pyridin-2-yl)imidazo[1,5-a]pyridin-6-yl)pyridin-2-yl)ethanamine;1-(6-(3-(6-(trifluoromethyl)pyridin-2-yl)imidazo[1,5-a]pyridin-6-yl)pyridin-2-yl)ethanamine;(Z)-1-(6-(3-(6-(trifluoromethyl)pyridin-2-yl)imidazo[1,5-a]pyridin-6-yl)pyridin-2-yl)ethanoneoxime;

tert-butyl(6-(6-acetylpyridin-2-yl)-1-(6-methylpyridin-2-yl)-1H-indazol-4-yl)(methyl)carbamate;(Z)-tert-butyl(6-(6-(1-(hydroxyimino)ethyl)pyridin-2-yl)-1-(6-methylpyridin-2-yl)-1H-indazol-4-yl)(methyl)carbamate;(Z)-1-(6-(4-(methylamino)-1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanoneoxime;1-(6-(1-(6-ethylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanone;1-(6-(1-(pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanone;(E)-1-(6-(1-(pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanone oxime;2-(aminomethyl)-6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-4-amine;N,N-dimethyl-1-(6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine;1-(6-(4-(dimethylamino)-1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanone;(E)-1-(6-(4-(dimethylamino)-1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanoneoxime;(E)-1-(6-(1-(6-ethylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanoneoxime; 6-(6-(6-acetylpyridin-2-yl)-1H-indazol-1-yl)picolinonitrile;(E)-methyl6-(6-(6-(1-(hydroxyimino)ethyl)pyridin-2-yl)-1H-indazol-1-yl)picolinate;1-(6-(1-(4-methylthiazol-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanone;1-(6-(4-fluoro-1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine;(S)-1-(6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine;1-(3-fluoro-6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine;methyl 3-amino-6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)picolinate;2,2,2-trifluoro-1-(6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanol;1-(6-(4-ethoxy-1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine;1-(6-(4-methoxy-1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine;3-amino-3-(6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)propan-1-ol;6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)picolinamide;2-(6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)acetonitrile;6-(6-(1-aminoethyl)pyridin-2-yl)-1-(6-methylpyridin-2-yl)-1H-indazol-4-ol;1-(6-(4-(cyclopropylmethoxy)-1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine;(4-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)thiazol-2-yl)methanamine;N-((6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)methyl)acetamide;2-(6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine;1-(6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)-3-(trifluoromethyl)pyridin-2-yl)ethanamine;2-(1-aminoethyl)-6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-4-amine;(1-methyl-4-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)-1H-imidazol-2-yl)methanol;2-amino-2-(6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)acetonitrile;2,2,2-trifluoro-1-(6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine;3-amino-3-(6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)propanoicacid; methyl3-amino-3-(6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)propanoate;1-(6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)cyclopropanamine;1-(6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)propan-1-amine;(R)-1-(6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)butan-1-amine;(S)-1-(6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)butan-1-amine;1-(3-chloro-6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine;2-amino-2-(6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)acetamide;1-(6-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)butan-1-amine;6-(6-(6-(1-aminopropyl)pyridin-2-yl)-1H-indazol-1-yl)picolinamide;2-(1-aminoethyl)-6-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-4-amine;2-amino-2-(6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanol;methyl2-amino-2-(6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)acetate;2-amino-2-(6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)aceticacid; 6-(6-(6-(1-aminobutyl)pyridin-2-yl)-1H-indazol-1-yl)picolinamide;1-(6-(3-(6-methylpyridin-2-yl)imidazo[1,5-a]pyridin-6-yl)pyridin-2-yl)propan-1-amine;1-(6-(3-(6-methylpyridin-2-yl)imidazo[1,5-a]pyridin-6-yl)pyridin-2-yl)butan-1-amine;2-(6-(6-(6-(1-aminoethyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)propan-2-ol;1-(6-(1-(6-(methoxymethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine;(6-(6-(6-(1-aminobutyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol;1-(3-methyl-6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine;1-(6-(1-(4-methylthiophen-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine;1-(6-(1-(6-propylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine;1-(6-(6-(6-(1-aminoethyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)ethanol;(4-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)oxazol-2-yl)methanamine;1-(6-(1-(6-(ieri-butyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine;1-(6-(1-(6-(aminomethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine;2(6-(6-(6-(1aminoethyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)-2-methylpropanenitrile;1-(6-(1-(6-(2-(methylsulfonyl)propan-2-yl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine;1-(6-(6-(6-(l-aminoethyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)cyclopropanecarbonitrile;(6-(6-(6-(aminomethyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol;2(6-(6-(6-(1-aminoethyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)propan-2-amine;1-(6-(3-(6-ethylpyridin-2-yl)imidazo[1,5-a]pyridin-6-yl)pyridin-2-yl)ethanamine;(6-(6-(6-(1-aminopropyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol;1-(6-(4-(1H-imidazol-2-yl)-1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine;1-(6-(1-(4-methylpyrimidin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine;1-(6-(1-(4-(trifluoromethyl)pyrimidin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine;2-(6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)propan-2-amine;1-(l-methyl-4-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)-1H-imidazol-2-yl)ethanol;(l-methyl-4-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)-1H-imidazol-2-yl)methanamine;2(6-(6-(6-(1-aminoethyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)-2-methylpropanamide;(6-(6-(6-(1-aminoethyl)pyridin-2-yl)imidazo[1,5-a]pyridin-3-yl)pyridin-2-yl)methanol;1-6-(1(6-methylpyridin-2-yl)-4-(thiazol-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine;1-(6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)cyclobutanecarbonitrile;1-(1-methyl-4-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)-1H-imidazol-2-yl)ethanamine;1-(6-methylpyridin-2-yl)-6-(pyridin-2-yl)-1H-indazole;(6-(6-(6-(1-aminoethyl)pyridin-2-yl)-4-methoxy-1H-indazol-1-yl)pyridin-2-yl)methanol;2-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-amine;(6-(6-(1-aminoethyl)pyridin-2-yl)-1-(6-(hydroxymethyl)pyridin-2-yl)-1H-indazol-4-yl)methanol;1-(4-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)thiazol-2-yl)ethanamine;1-(6-(8-chloro-3-(6-(trifluoromethyl)pyridin-2-yl)imidazo[1,5-a]pyridin-6-yl)pyridin-2-yl)ethanamine;1-(6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)cyclobutanecarboxamide;1-(6-methylpyridin-2-yl)-6-(6-(3,3,3-trifluoropropyl)pyridin-2-yl)-1H-indazole;2-(6-(6-(6-(1-aminoethyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)ethanol;1-(6-(1-(4,6-dimethylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine;6-(6-(1aminoethyl)pyridin-2-yl)-1-(6-(hydroxymethyl)pyridin-2-yl)-N-methyl-1H-indazole-4-carboxamide;1-(6-(8-fluoro-3-(6-(trifluoromethyl)pyridin-2-yl)imidazo[1,5-a]pyridin-6-yl)pyridin-2-yl)ethanamine;(S)-(6-(6-(6-(1-aminopropyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol;1-(6-(1-(6-methylpyridin-2-yl)-4-(1H-pyrazol-3-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine;(4-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)thiazol-2-yl)methanol;(6-(6-(6-(1-aminoethyl)pyridin-2-yl)-4-fluoro-1H-indazol-1-yl)pyridin-2-yl)methanol;(R)-(6-(6-(6-(1-aminopropyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol;6-(1-methyl-1H-imidazol-4-yl)-1-(6-methylpyridin-2-yl)-1H-indazole;(6-(6-(6-ethylpyridin-2-yl)-4-(5-methyl-1,3,4-oxadiazol-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol;1-(6-(6-((S)-1-aminobutyl)pyridin-2-yl)-1-(6-(hydroxymethyl)pyridin-2-yl)-1H-indazol-4-yl)pyrrolidin-3-ol;(S)-(6-(6-(6-(1-aminopropyl)pyridin-2-yl)-1H-indazol-1-yl)pyrazin-2-yl)methanol;(1-(6-(6-((S)-1-aminobutyl)pyridin-2-yl)-1-(6-(hydroxymethyl)pyridin-2-yl)-1H-indazol-4-yl)pyrrolidin-2-yl)methanol;(S)-(6-(6-(6-(1-aminobutyl)pyridin-2-yl)-4-(methylamino)-1H-indazol-1-yl)pyridin-2-yl)methanol;(S)-(6-(6-(6-(1-aminoethyl)pyridin-2-yl)-4-(oxazol-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol;(S)-(6-(6-(6-(1-aminobutyl)pyridin-2-yl)-1H-indazol-1-yl)pyrazin-2-yl)methanol;(S)-(6-(6-(6-(1-aminopropyl)pyridin-2-yl)-4-(1-methyl-1H-pyrazol-3-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol;(S)-(6-(6-(6-(1-aminobutyl)pyridin-2-yl)-4-(2-methoxyethoxy)-1H-indazol-1-yl)pyridin-2-yl)methanol;(6-(6-(6-((1R,2R)-1-amino-2-fluorobutyl)pyridin-2-yl)-4-(2-methoxyethoxy)-1H-indazol-1-yl)pyridin-2-yl)methanol;(S)-(6-(6-(6-(1-aminobutyl)pyridin-2-yl)-4-(ethylamino)-1H-indazol-1-yl)pyridin-2-yl)methanol;(S)-(6-(6-(6-(1-aminobutyl)pyridin-2-yl)-4-(1-methyl-1H-pyrazol-3-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol;(S)-1-(6-(6-(1-aminobutyl)pyridin-2-yl)-1-(6-(hydroxymethyl)pyridin-2-yl)-1H-indazol-4-yl)piperidin-4-ol;1-(6-(6-((S)-1-aminobutyl)pyridin-2-yl)-1-(6-(hydroxymethyl)pyridin-2-yl)-1H-indazol-4-yl)piperidin-3-ol;(S)-(6-(6-(6-(1-aminoethyl)pyridin-2-yl)-1H-indazol-1-yl)pyrazin-2-yl)methanol;(S)-(6-(6-(6-(1-aminobutyl)pyridin-2-yl)-4-(3,3-difluoroazetidin-1-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol;(S)-(6-(6-(6-(1-aminopropyl)pyridin-2-yl)-4-(methylamino)-1H-indazol-1-yl)pyridin-2-yl)methanol;(S)-1-(6-(1-(4-(difluoromethyl)pyrimidin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)butan-1-amine;(S)-(6-(6-(6-(1-aminoethyl)pyridin-2-yl)-4-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol;(S)-(6-(6-(6-(1-aminobutyl)pyridin-2-yl)-4-(fluoromethyl)-1H-indazol-1-yl)pyridin-2-yl)methanol;(S)-1-(4-(6-(6-(1-aminobutyl)pyridin-2-yl)-1-(6-(hydroxymethyl)pyridin-2-yl)-1H-indazol-4-yl)-5,6-dihydropyridin-1(2H)-yl)ethanone;(S)-(6-(6-(6-(1-aminobutyl)pyridin-2-yl)-4-methoxy-1H-indazol-1-yl)pyrazin-2-yl)methanol;(S)-(6-(6-(6-(1-aminoethyl)pyridin-2-yl)-4-(5-methyl-,3,4-thiadiazol-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol;(S)-(6-(6-(6-(1-aminobutyl)pyridin-2-yl)-4-chloro-1H-indazol-1-yl)pyridin-2-yl)methanol;(S)-(1-(6-(6-(1-aminobutyl)pyridin-2-yl)-1-(6-(hydroxymethyl)pyridin-2-yl)-1H-indazol-4-yl)-3-(chloromethyl)azetidin-3-yl)methanol;(S) 66-(6-(1-aminoethyl)pyridin-2-yl)-4-(1-methy-1H-midazol-4-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol;(S)-(6-(6-(6-(1-aminobutyl)pyridin-2-yl)-4-(3,3-difluoropyrrolidin-1-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol;(6-(6-(6-((S)-1-aminobutyl)pyridin-2-yl)-4-(2-methylmorpholino)-1H-indazol-1-yl)pyridinyl)methanol;(S)-(6-(6-(6-(1-aminobutyl)pyridin-2-yl)-4-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol;(6-(6-(6-((1R,2S)-1-amino-2-fluorobutyl)pyridin-2-yl)-4-(2-methoxyethoxy)-1H-indazol-1-yl)pyridin-2-yl)methanol;(S)-(6-(6-(6-(1-aminoethyl)pyridin-2-yl)-4-(pyrimidin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol;(S)-(6-(6-(6-(1-aminobutyl)pyridin-2-yl)-4-(difluoromethyl)-1H-indazol-1-yl)pyridin-2-yl)methanol;(S)-(6-(6-(1-aminobutyl)pyridin-2-yl)-1-(6-(hydroxymethyl)pyridin-2-yl)-1H-indazol-4-yl)methanol;(S)-(6-(6-(6-(1-aminobutyl)pyridin-2-yl)-4-(3-methoxypropoxy)-1H-indazol-1-yl)pyridin-2-yl)methanol;(S)-(6-(6-(6-(1-aminopentyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol;(S)-(6-(6-(6-(1-aminoethyl)pyridin-2-yl)-4-(1H-imidazol-1-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol;(S)-(6-(6-(6-(1-aminobutyl)pyridin-2-yl)-4-(3,6-dihydro-2H-pyran-4-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol;(S)-(6-(6-(6-(1-aminopropyl)pyridin-2-yl)-4-(3-methoxypropoxy)-1H-indazol-1-yl)pyridin-2-yl)methanol;(S)-(6-(6-(6-(1-aminoethyl)pyridin-2-yl)-4-(1,5-dimethyl-1H-pyrazol-3-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol;(S)-(6-(6-(6-(1-aminoethyl)pyridin-2-yl)-4-(5-methyl-1H-pyrazol-3-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol;(S)-(6-(6-(6-(1-aminobutyl)pyridin-2-yl)-4-(methoxymethyl)-1H-indazol-1-yl)pyridin-2-yl)methanol;(S)-(6-(6-(6-(amino(cyclopropyl)methyl)pyridin-2-yl)-4-methoxy-1H-indazol-1-yl)pyrazin-2-yl)methanol;(6-(6-(6-((S)-1-aminobutyl)pyridin-2-yl)-4-(2,6-dimethylmorpholino)-1H-indazol-1-yl)pyridin-2-yl)methanol;(S)-(6-(6-(4-(1-aminobutyl)pyrimidin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol;3-((6-(6-((S)-1-aminobutyl)pyridin-2-yl)-1-(6-(hydroxymethyl)pyridin-2-yl)-1H-indazol-4-yl)amino)-2-(chloromethyl)prop anoic acid;(S)-(6-(6-(6-(1-aminobutyl)pyridin-2-yl)-4-((difluoromethoxy)methyl)-1H-indazol-1-yl)pyridin-2-yl)methanol;(S)-(6-(6-(6-(1-aminobutyl)pyridin-2-yl)-4-(morpholinomethyl)-1H-indazol-1-yl)pyridin-2-yl)methanol;(S)-4-(6-(6-(1-aminobutyl)pyridin-2-yl)-1-(6-(hydroxymethyl)pyridin-2-yl)-1H-indazol-4-yl)thiomorpholine1,1-dioxide;(S)-(6-(6-(6-(1-amino-4,4,4-trifluorobutyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol;(S)-(6-(6-(6-(1-aminobutyl)pyridin-2-yl)-4-thiomorpholino-1H-indazol-1-yl)pyridin-2-yl)methanol;1-(6-(6-(6-((S)-1-aminoethyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)ethanol;(S)-(6-(6-(6-(1-aminobutyl)pyridin-2-yl)-4-ethoxy-1H-indazol-1-yl)pyrazin-2-yl)methanol;(S)-(6-(6-(6-(1-aminoethyl)pyridin-2-yl)-4-(1-methyl-1H-pyrazol-3-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol;(S)-(6-(6-(6-(1-aminoethyl)pyridin-2-yl)-4-(2-methylthiazol-4-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol;(S)-(6-(6-(6-(1-aminopropyl)pyridin-2-yl)-4-ethoxy-1H-indazol-1-yl)pyrazin-2-yl)methanol;(S)-(6-(6-(6-(1-aminoethyl)pyridin-2-yl)-4-(3-methoxypropoxy)-1H-indazol-1-yl)pyridin-2-yl)methanol;(S)-(6-(6-(6-(amino(cyclopropyl)methyl)pyridin-2-yl)-4-ethoxy-1H-indazol-1-yl)pyrazin-2-yl)methanol;(S)-(6-(6-(6-(1-aminoethyl)pyridin-2-yl)-4-(1H-1,2,4-triazolyl)H-indazol-1-yl)pyridin-2-yl)methanol;(S)-2-(6-(6-(1-aminoethyl)pyridin-2-yl)-1-(6-(hydroxymethyl)pyridin-2-yl)-1H-indazol-4-yl)thiazole-4-carbonitrile;(S)-(6-(6-(6-(1-aminoethyl)pyridin-2-yl)-4-(isothiazol-3-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol;(S)-(6-(6-(6-(amino(cyclobutyl)methyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol;(S)-(6-(6-(6-(1-aminobutyl)pyridin-2-yl)-4-(tetrahydro-2H-pyran-4-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol;(6-(6-(6-((1R,2S)-1-amino-2-fluorobutyl)pyridin-2-yl)-4-ethoxy-1H-indazol-1-yl)pyridin-2-yl)methanol;(S)-(6-(6-(6-(1-aminobutyl)pyridin-2-yl)-4-morpholino-1H-indazol-1-yl)pyridin-2-yl)methanol;(6-(6-(6-((1R,2R)-1-amino-2-fluorobutyl)pyridin-2-yl)-4-ethoxy-1H-indazol-1-yl)pyridin-2-yl)methanol;1-(6-(6-(6-((S)-1-aminobutyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)ethanol;(S)-(6-(6-(6-(1-aminobutyl)pyridin-2-yl)-4-(3,3-dimethylazetidin-1-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol;(S)-(6-(6-(6-(1-amino-4,4,4-trifluorobutyl)pyridin-2-yl)-4-methoxy-1H-indazol-1-yl)pyridin-2-yl)methanol;(S)-(6-(6-(6-(1-aminopropyl)pyridin-2-yl)-4-methoxy-1H-indazol-1-yl)pyrazin-2-yl)methanol;(S)-(6-(6-(6-(1-amino-3,3-difluorobutyl)pyridin-2-yl)-4-ethoxy-1H-indazol-1-yl)pyridin-2-yl)methanol;(S)-1-(6-(4-methoxy-1-(4-(trifluoromethyl)pyrimidin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)butan-1-amine;(6-(6-(6-(amino(oxetan-3-yl)methyl)pyridin-2-yl)-4-ethoxy-1H-indazol-1-yl)pyridin-2-yl)methanol;(S)-1-(6-(4-ethoxy-1-(4-(trifluoromethyl)pyrimidin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)butan-1-amine;(6-{6-[6-((S)-1-Amino-ethyl)-pyridin-2-yl]-4-fluoro-indazol-1-yl}-pyridin-2-yl)-methanol;(S)-(6-(6-(6-(1-aminoethyl)pyridin-2-yl)-4-phenyl-1H-indazol-1-yl)pyridin-2-yl)methanol;(S)-(6-(6-(6-(1-amino-3,3-difluorobutyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol;(S)-(6-(6-(6-(1-aminoethyl)pyridin-2-yl)-4-(5-methylthiazol-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol;(6-(6-(6-((S)-1-aminobutyl)pyridin-2-yl)-4-(piperidin-3-ylmethoxy)-1H-indazol-1-yl)pyridin-2-yl)methanol;(6-{6-[6-((S)-1-Amino-butyl)-pyridin-2-yl]-4-isopropoxy-indazol-1-yl}-pyridin-2-yl)-methanol;(S)-(6-(6-(6-(1-aminoethyl)pyridin-2-yl)-4-(pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol;1-(6-(6-((S)-1-aminobutyl)pyridin-2-yl)-1-(6-(hydroxymethyl)pyridin-2-yl)-1H-indazol-4-yl)pyrrolidine-3-carboxylicacid;(S)-(6-(6-(6-(1-aminobutyl)pyridin-2-yl)-4-(pyrrolidin-1-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol;(6-(6-(6-(amino(oxetan-3-yl)methyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol;(R)-(6-(6-(4-(1-aminobutyl)pyrimidin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol;1-amino-1-(6-(1-(6-(hydroxymethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)butan-2-ol;(6-{6-[6-((S)-1-Amino-butyl)-pyridin-2-yl]-4-fluoro-indazol-1-yl}-pyridin-2-yl)-methanol;4-amino-4-(6-(1-(6-(hydroxymethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)butan-2-ol;(S)-(6-(6-(6-(1-aminobutyl)pyridin-2-yl)-4-(4-methylpiperazin-1-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol;(S)-(6-(6-(6-(1-amino-4-methoxybutyl)pyridin-2-yl)-4-methoxy-1H-indazol-1-yl)pyridin-2-yl)methanol;(S)-(6-(6-(6-(1-amino-4,4,4-trifluorobutyl)pyridin-2-yl)-4-ethoxy-1H-indazol-1-yl)pyridin-2-yl)methanol;(S)-6-(6-(1-aminobutyl)pyridin-2-yl)-1-(6-(hydroxymethyl)pyridin-2-yl)-1H-indazole-4-carbonitrile;(S)-1-(6-(1-(4-(difluoromethyl)pyrimidin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)propan-1-amine;(S)-(6-(6-(6-(1-amino-4-methoxybutyl)pyridin-2-yl)-4-ethoxy-1H-indazol-1-yl)pyridin-2-yl)methanol;(S)-(6-(6-(6-(1-aminobutyl)pyridin-2-yl)-4-(2,2,2-trifluoroethoxy)-1H-indazol-1-yl)pyridin-2-yl)methanol;(S)-1-(4-(6-(6-(1-aminobutyl)pyridin-2-yl)-1-(6-(hydroxymethyl)pyridin-2-yl)-1H-indazol-4-yl)piperidin-1-yl)ethanone;1-amino-1-(6-(1-(6-(hydroxymethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)butan-2-ol;(S)-(6-(6-(6-(1-aminoethyl)pyridin-2-yl)-4-(4-(trifluoromethyl)oxazol-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol;(S)-(6-(6-(6-(1-aminobutyl)pyridin-2-yl)-4-((dimethylamino)methyl)-1H-indazol-1-yl)pyridin-2-yl)methanol;(S)-(6-(6-(6-(1-aminobutyl)pyridin-2-yl)-4-((3-chloro-2,2-dimethylpropyl)amino)-1H-indazol-1-yl)pyridin-2-yl)methanol;(S)-(6-(6-(6-(1-aminobutyl)pyridin-2-yl)-4-ethoxy-1H-indazol-1-yl)pyridin-2-yl)methanol;(S)-1-(6-(1-(6-(fluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)butan-1-amine;(S)-(6-(6-(6-(1-aminobutyl)pyridin-2-yl)-4-(azetidin-1-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol;(S)-(6-(6-(6-(1-aminobutyl)pyridin-2-yl)-4-(4,4-difluoropiperidin-1-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol;(S)-1-(6-(1-(6-(difluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)butan-1-amine;(S)-(6-(6-(6-(1-aminobutyl)pyridin-2-yl)-4-(3,3-difluoropiperidin-1-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol;(S)-1-(6-(6-(1-aminobutyl)pyridin-2-yl)-1-(6-(hydroxymethyl)pyridin-2-yl)-1H-indazol-4-yl)azetidine-3-carboxylicacid;(6-(6-(6-(1-amino-2-(methylthio)ethyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol;(R)-1-(6-(6-(6-((S)-1-aminobutyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)-2,2,2-trifluoroethanol;(S)-(6-(6-(6-(1-aminoethyl)pyridin-2-yl)-4-(4-methylthiazol-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol;(S)-(6-(6-(6-(1-amino-3-methylbutyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol;(R)-(6-(6-(6-(amino(phenyl)methyl)pyridin-2-yl)-4-ethoxy-1H-indazol-1-yl)pyridin-2-yl)methanol;(6-(6-(6-((1R,2R)-1-amino-2-methoxybutyl)pyridin-2-yl)-4-ethoxy-1H-indazol-1-yl)pyridin-2-yl)methanol;(S)-(6-(6-(6-(1-aminobutyl)pyridin-2-yl)-4-(2-cyclopropylethoxy)-1H-indazol-1-yl)pyridin-2-yl)methanol;(S)-(6-(6-(6-(1-aminobutyl)pyridin-2-yl)-4-methoxy-1H-indazol-1-yl)pyridin-2-yl)methanol;(S)-(6-(6-(6-(1-aminobutyl)pyridin-2-yl)-4-(tifluoromethoxy)-1H-indazol-1-yl)pyridin-2-yl)methanol;(S)-(6-(6-(6-(1-aminoethyl)pyridin-2-yl)-4-(4,5-dihydrooxazol-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol;4-amino-4-(6-(1-(6-(hydroxymethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)butan-2-ol;(S)-(6-(6-(6-(1-aminobutyl)pyridin-2-yl)-4-(difluoromethoxy)-1H-indazol-1-yl)pyrazin-2-yl)methanol;(S)-(6-(6-(6-(1-(methylamino)butyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol;(6-(6-(6-((S)-1-aminoethyl)pyridin-2-yl)-4-(4-methyl-4,5-dihydrooxazol-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol;(S)-(6-(6-(6-(1-aininoethyl)pyridin-2-yl)-4-(1-(fluoromethyl)-1H-pyrazol-4-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol;(S)-1-(6-(1-(6-(difluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine;2-amino-2-(6-(1-(6-(hydroxymethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanol;(S)-(6-(6-(6-(1-amino-3-methylbut-3-en-1-yl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol;(S)-1-(6-(1-(4-(trifluoromethyl)pyrimidin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)butan-1-amine;(6-(6-(6-(1-amino-2-(methylsulfonyl)ethyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol;1-(6-(6-((S)-1-aminobutyl)pyridin-2-yl)-1-(6-(hydroxymethyl)pyridin-2-yl)-1H-indazol-4-yl)piperidine-3-carboxylicacid;(S)-6-(6-(1-aminopropyl)pyridin-2-yl)-1-(6-(hydroxymethyl)pyridin-2-yl)-1H-indazole-4-carbonitrile;(S)-(6-(6-(6-(1-aminoethyl)pyridin-2-yl)-4-(4,5-dimethylthiazol-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol;(S)-(6-(6-(6-(1-aminobutyl)pyridin-2-yl)-4-(piperidin-1-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol;(6-(6-(6-(1-amino-2-cyclopropylethyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol;1-(6-(6-(6-((S)-1-aminoethyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)ethanol;(6-{6-[6-((S)-1-Amino-butyl)-pyridin-2-yl]-4-fluoro-indazol-1-yl}-pyridin-2-yl)-methanol;1-(6-(1-(6-methylpyridin-2-yl)-4-(oxazol-5-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine;(S)-(6-(6-(4-(1-aminoethyl)pyrimidin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol;(S)-6-(6-(1-aminoethyl)pyridin-2-yl)-1-(6-(hydroxymethyl)pyridin-2-yl)-1H-indazole-4-carbonitrile;(6-(6-(6-(amino(cyclopropyl)methyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol;(S)-1-(6-(1-(6-(difluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)propan-1-amine;(S)-6-(6-(1-aminoethyl)pyridin-2-yl)-N-(1-hydroxy-2-methylpropan-2-yl)-1-(6-(hydroxymethyl)pyridin-2-yl)-1H-indazole-4-carboxamide;(S)-1-(6-(1-(4-(difluoromethyl)pyrimidin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine;1-(6-(1-(6-methylpyridin-2-yl)-4-(oxazol-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine;(S)-(6-(6-(6-(1-aminoethyl)pyridin-2-yl)-4-(4-(trifluoromethyl)thiazol-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol;(6-(6-(6-(1-amino-2-methoxyethyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol;2-amino-2-(6-(1-(6-(hydroxymethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)-N,N-dimethylacetamide;(S)-(6-(6-(6-(1-aminoethyl)pyridin-2-yl)-4-(thiazol-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol;(S)-1-(6-(6-(6-((S)-1-aminobutyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)-2,2,2-trifluoroethanol;(S)-(6-(6-(6-(1-aminoethyl)pyridin-2-yl)-4-(5-(trifluoromethyl)thiazol-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol;(S)-1-(6-(6-(1-aminobutyl)pyridin-2-yl)-1-(6-(hydroxymethyl)pyridin-2-yl)-1H-indazol-4-yl)piperidine-4-carboxylicacid;(S)-(6-(6-(6-(1-aminoethyl)pyridin-2-yl)-1H-indazol-1-yl)-3-fluoropyridin-2-yl)methanol;(6-(6-(6-((1R,2S)-1-amino-2-methoxybutyl)pyridin-2-yl)-4-ethoxy-1H-indazol-1-yl)pyridin-2-yl)methanol;(S)-1-(6-(1-(6-(trifluoromethyl)pyrazin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)butan-1-amine;(S)-6-(6-(6-(1-aminobutyl)pyridin-2-yl)-1H-indazol-1-yl)picolinaldehyde;(S)-(6-(6-(6-(1-aminoethyl)pyridin-2-yl)-4-(3-(trifluoromethyl)-1H-pyrazol-1-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol;6-(6-((S)-1-aminoethyl)pyridin-2-yl)-N-(2-aminopropyl)-1-(6-(hydroxymethyl)pyridin-2-yl)-1H-indazole-4-carboxamide;(S)-(6-(6-(6-(1-aminoethyl)pyridin-2-yl)-4-(1H-pyrazol-3-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol;1-(6-(1-(6-(hydroxymethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)butan-1-ol;1-(6-(1-(6-(hydroxymethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)butan-1-ol;(6-(6-(6-(1-amino-2-(3-methyloxetan-3-yl)ethyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol;3,3,3-trifluoro-1-(6-(1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)propan-1-amine;1-(6-(4-(5-methyl-1,3,4-oxadiazol-2-yl)-1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine;1-(6-(1-(6-methylpyrazin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethanamine;6-{6-[6-((S)-1-Amino-ethyl)-pyridin-2-yl]-indazol-1-yl}-pyridine-2-carboxylicacid;2-amino-2-(6-(1-(6-(hydroxymethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)acetonitrile;2-amino-2-(6-(1-(6-(hydroxymethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)acetamide;4-(6-(6-(1-aminoethyl)pyridin-2-yl)-1H-indazol-1-yl)pyrimidine-2-carbonitrile;(6-(6-(3-(1-aminoethyl)phenyl)-1H-indazol-1-yl)pyridin-2-yl)methanol;(6-(6-(6-(1-aminoethyl)-3-fluoropyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol;(R)-(6-(6-(4-(1-aminoethyl)pyrimidin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol;(S)-(6-(6-(6-(1-aminoethyl)pyridin-2-yl)-1H-indazol-1-yl)-5-fluoropyridin-2-yl)methanol;(S)-(6-(6-(6-(1-(dimethylamino)butyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol;1-(6-(6-(6-((S)-1-aminobutyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)ethanol;2-amino-2-(6-(1-(6-(hydroxymethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)-N-methylacetamide;(6-(6-(6-(1-amino-2-(methylsulfinyl)ethyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol;(6-(6-(6-((S)-1-aminobutyl)pyridin-2-yl)-4-(1-methoxyethyl)-1H-indazol-1-yl)pyridin-2-yl)methanol;(S)-4-amino-4-(6-(1-(6-(hydroxymethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)butan-1-ol;(S)-(6-(6-(6-(1-aminobut-3-en-1-yl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol;(S)-4-amino-4-(6-(1-(6-(hydroxymethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)butan-2-one;(S)-1-(6-(4-chloro-1-(4-(difluoromethyl)pyrimidin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)butan-1-amine;(6-(6-(6-(pyrrolidin-2-yl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol;(S)-4-(6-(6-(1-aminobutyl)pyridin-2-yl)-1-(6-(hydroxymethyl)pyridin-2-yl)-1H-indazol-4-yl)-2-methylbut-3-yn-2-ol;(S)-(6-(6-(6-(1-aminoethyl)pyridin-2-yl)-4-(2-(trifluoromethyl)thiazol-4-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol;(S)-1-(6-(1-(4-(difluoromethyl)pyrimidin-2-yl)-4-methoxy-1H-indazol-6-yl)pyridin-2-yl)butan-1-amine;(S)-(6-(6-(6-(1-aminopent-3-yn-1-yl)pyridin-2-yl)-4-ethoxy-1H-indazol-1-yl)pyridin-2-yl)methanol;(S)-(6-(6-(6-(amino(phenyl)methyl)pyridin-2-yl)-4-ethoxy-1H-indazol-1-yl)pyridin-2-yl)methanol;(6-(6-(6-((S)-1-aminobutyl)pyridin-2-yl)-4-((S)-pyrrolidin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol;(6-(6-(6-((S)-1-aminobutyl)pyridin-2-yl)-4-(tetrahydrofuran-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol;(S)-4-(6-(6-(1-aminobutyl)pyridin-2-yl)-1-(6-(hydroxymethyl)pyridin-2-yl)-1H-indazol-4-yl)morpholin-3-one;(S)-(6-(6-(4-(1-aminobutyl)pyrimidin-2-yl)-4-methoxy-1H-indazol-1-yl)pyridin-2-yl)methanol;(S)-(6-(6-(6-(1-amino-4-methoxybutyl)pyridin-2-yl)-4-(1-methyl-1H-pyrazol-3-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol;(R)-(6-(6-(4-(1-aminobutyl)pyrimidin-2-yl)-4-methoxy-1H-indazol-1-yl)pyridin-2-yl)methanol;(S)-(6-(6-(6-(1-aminoethyl)pyridin-2-yl)-4-(5-(trifluoromethyl)-1H-pyrazol-3-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol;(S)-(6-(6-(6-(1-aminobutyl)pyridin-2-yl)-4-(pyrimidin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol;deutero(S)-(6-(6-(6-(1-aminobutyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol;(S)-(6-(6-(6-(1-aminoethyl)pyridin-2-yl)-4-(5-fluoro-2-yl)methanol;(S)-(4-(6-(6-(1-aminobutyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol;(S)-(3-(6-(6-(1-aminobutyl)pyridin-2-yl)-1H-indazol-1-yl)phenyl)methanol;(S)-(6-(6-(6-(1-aminoethyl)pyridin-2-yl)-4-(5-methyloxazol-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol;(S)-(6-(6-(6-(1-aminobutyl)pyridin-2-yl)-4-(1H-1,2,3-triazol-1-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol;(S)-(6-(6-(6-(1-aminobutyl)pyridin-2-yl)-4-((trifluoromethoxy)methyl)-1H-indazol-1-yl)pyridin-2-yl)methanol;(S)-(6-(6-(6-(1-aminoethyl)pyridin-2-yl)-4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol;(S)-(6-(6-(6-(1-aminoethyl)pyridin-2-yl)-4-(1-(difluoromethyl)-1H-pyrazol-5-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol;(S)-(6-(6-(6-(1-aminoethyl)pyridin-2-yl)-4-(pyrazin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol;(S)-(6-(6-(4-(1-aminopentyl)pyrimidin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol;(R)-3-amino-3-(6-(1-(6-(hydroxymethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)propanenitrile;(S)-4-amino-4-(6-(1-(6-(hydroxymethyl)pyridin-2-yl)-4-methoxy-1H-indazol-6-yl)pyridin-2-yl)butan-1-ol;(S)-4-amino-4-(6-(4-ethoxy-1-(6-(hydroxymethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)butan-1-ol;(S)-(6-(6-(6-(1-aminobutyl)pyridin-2-yl)-4-(2-methoxyethoxy)-1H-indazol-1-yl)pyrazin-2-yl)methanol;(S)-(6-(6-(6-(1-aminoethyl)pyridin-2-yl)-4-(2-methoxyethoxy)-1H-indazol-1-yl)pyrazin-2-yl)methanol;(S)-(6-(6-(4-(1-aminobutyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol;(S)-(6-(6-(6-(1-aminobutyl)pyridin-2-yl)-4-(5-methyloxazol-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol;(S)-(6-(6-(4-(1-aminobutyl)pyrimidin-2-yl)-4-ethoxy-1H-indazol-1-yl)pyridin-2-yl)methanol;(R)-(6-(6-(4-(1-aminobutyl)pyrimidin-2-yl)-4-ethoxy-1H-indazol-1-yl)pyridin-2-yl)methanol;(S)-2-((6-(6-(1-aminobutyl)pyridin-2-yl)-1-(6-(hydroxymethyl)pyridin-2-yl)-1H-indazol-4-yl)oxy)ethanol;(S)-(6-(6-(6-(1-aminobutyl)pyridin-2-yl)-4-(1,5-dimethyl-1H-pyrazol-3-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol;(S)-(2-(6-(6-(1-aminobutyl)pyridin-2-yl)-1H-indazol-1-yl)pyrimidin-4-yl)methanol;(S)-(6-(6-(6-(1-aminopropyl)pyridin-2-yl)-4-(2-methoxyethoxy)-1H-indazol-1-yl)pyrazin-2-yl)methanol;2-(6-(6-((S)-1-aminobutyl)pyridin-2-yl)-1-(6-(hydroxymethyl)pyridin-2-yl)-1H-indazol-4-yl)-3-chloropropan-1-ol;(S)-(6-(6-(6-(1-aminoethyl)pyridin-2-yl)-4-(2-methoxyethoxy)-1H-indazol-1-yl)pyridin-2-yl)methanol;(S)-(6-(6-(6-(1-aminopropyl)pyridin-2-yl)-4-(2-methoxyethoxy)-1H-indazol-1-yl)pyridin-2-yl)methanol;(S)-(6-(6-(6-(amino(cyclopropyl)methyl)pyridin-2-yl)-4-(2-methoxyethoxy)-1H-indazol-1-yl)pyridin-2-yl)methanol;(S)-(6-(6-(6-(1-amino-3,3-difluorobutyl)pyridin-2-yl)-4-(2-methoxyethoxy)-1H-indazol-1-yl)pyridin-2-yl)methanol;(S)-4-amino-4-(6-(1-(6-(hydroxymethyl)pyridin-2-yl)-4-(1-methyl-1H-pyrazol-3-yl)-1H-indazol-6-yl)pyridin-2-yl)butan-1-ol;(R)-(6-(6-(6-(1-aminopropyl)pyridin-2-yl)-4-(1,5-dimethyl-1H-pyrazol-3-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol;(R)-(6-(6-(6-(1-amino-2-fluoroethyl)pyridin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol;(S)-1-(6-(1-(6-methylpyrazin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)butan-1-amine;(S)-3-amino-3-(6-(1-(6-(hydroxymethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)propanenitrile;(S)-4-amino-4-(6-(1-(6-(hydroxymethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)butanenitrile;(S)-(6-(6-(2-(1-aminobutyl)pyrimidin-4-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol;(4R)-4-amino-3-fluoro-4-(6-(1-(6-(hydroxymethyl)pyridin-2-yl)-4-(2-methoxyethoxy)-1H-indazol-6-yl)pyridin-2-yl)butan-1-ol;(R)-(6-(6-(6-(1-amino-2-fluoroethyl)pyridin-2-yl)-4-(1,5-dimethyl-1H-pyrazol-3-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol;(S)-4-amino-4-(6-(1-(6-(hydroxymethyl)pyridin-2-yl)-4-(2-methoxyethoxy)-1H-indazol-6-yl)pyridin-2-yl)butan-1-ol;(4R)-4-amino-3-fluoro-4-(6-(1-(6-(hydroxymethyl)pyridin-2-yl)-4-(2-methoxyethoxy)-1H-indazol-6-yl)pyridin-2-yl)butan-1-ol;(4S)-4-amino-3-fluoro-4-(6-(1-(6-(hydroxymethyl)pyridin-2-yl)-4-(2-methoxyethoxy)-1H-indazol-6-yl)pyridin-2-yl)butan-1-ol;(R)-(6-(6-(2-(1-aminobutyl)pyrimidin-4-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol;(S)-4-amino-4-(6-(4-(1,5-dimethyl-1H-pyrazol-3-yl)-1-(6-(hydroxymethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)butan-1-ol;(S)-(6-(6-(6-(1-aminoethyl)pyridin-2-yl)-4-(pyrimidin-4-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol;(S)-(6-(6-(6-(1-aminoethyl)pyridin-2-yl)-4-(pyridazin-3-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol;(R)-(6-(6-(6-(1-amino-2-fluoroethyl)pyridin-2-yl)-4-(2-methoxyethoxy)-1H-indazol-1-yl)pyridin-2-yl)methanol;(S)-4-amino-4-(6-(1-(6-(hydroxymethyl)pyrazin-2-yl)-4-(2-methoxyethoxy)-1H-indazol-6-yl)pyridin-2-yl)butan-1-ol;(S)-(6-(6-(4-(1-aminobutyl)pyrimidin-2-yl)-4-(2-methoxyethoxy)-1H-indazol-1-yl)pyridin-2-yl)methanol;(6-(6-(6-(1-aminocyclobutyl)pyridin-2-yl)-4-(2-methoxyethoxy)-1H-indazol-1-yl)pyridin-2-yl)methanol;(R)-(6-(6-(4-(1-aminobutyl)pyrimidin-2-yl)-4-(2-methoxyethoxy)-1H-indazol-1-yl)pyridin-2-yl)methanol;(4S)-4-amino-3-fluoro-4-(6-(1-(6-(hydroxymethyl)pyridin-2-yl)-4-(2methoxyethoxy)-1H-indazol-6-yl)pyridin-2-yl)butan-1-ol;(S)-3-((6-(6-(1-aminobutyl)pyridin-2-yl)-1-(6-(hydroxymethyl)pyridin-2-yl)-1H-indazol-4-yl)oxy)propan-1-ol;(S)-3-((6-(6-(1-aminopropyl)pyridin-2-yl)-1-(6-(hydroxymethyl)pyridin-2-yl)-1H-indazol-4-yl)oxy)propan-1-ol;(S)-3-((6-(6-(1-aminoethyl)pyridin-2-yl)-1-(6-(hydroxymethyl)pyridin-2-yl)-1H-indazol-4-yl)oxy)propan-1-ol ;(6-(6-(6-((S)-1-aminobutyl)pyridin-2-yl)-4-((2S,5R)-5-methyltetrahydrofuran-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol;(6-(6-(6-((S)-1-aminobutyl)pyridin-2-yl)-4-((2R,5R)-5-methyltetrahydrofuran-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol;(6-(6-(6-((S)-1-aminobutyl)pyridin-2-yl)-4-(tetrahydrofuran-3-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol;(R)-(6-(6-(6-(1-aminobutyl)pyrazin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol;(6-(6-(6-((1R)-1-amino-2-fluoropropyl)pyridin-2-yl)-4-(2-methoxyethoxy)-1H-indazol-1-yl)pyridin-2-yl)methanol;(6-(6-(6-(1-aminocyclobutyl)pyridin-2-yl)-4-(2-methoxyethoxy)-1H-indazol-1-yl)pyrazin-2-yl)methanol;(6-(6-(6-(1-aminocyclopentyl)pyridin-2-yl)-4-(2-methoxyethoxy)-1H-indazol-1-yl)pyridin-2-yl)methanol;(6-(6-(6-(3-aminotetrahydrofuran-3-yl)pyridin-2-yl)-4-(2-methoxyethoxy)-1H-indazol-1-yl)pyridin-2-yl)methanol;(S)-1-((6-(6-(1-aminobutyl)pyridin-2-yl)-1-(6-(hydroxymethyl)pyridin-2-yl)-1H-indazol-4-yl)oxy)-2-methylpropan-2-ol;(S)-(6-(6-(6-(1-aminobutyl)pyrazin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol;(6-(6-(6-((1S)-1-amino-2-fluoropropyl)pyridin-2-yl)-4-(2-methoxyethoxy)-1H-indazol-1-yl)pyridin-2-yl)methanol;(S)-(6-(6-(6-(1-aminoethyl)pyridin-2-yl)-4-(3-methyl-1H-pyrazol-1-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol;(S)-(6-(6-(6-(1-aminoethyl)pyridin-2-yl)-4-(1H-pyrazol-1-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol;(S)-(4-(6-(6-(1-aminobutyl)pyridin-2-yl)-1H-indazol-1-yl)pyrimidin-2-yl)methanol;(6-(6-(8-amino-8-methyl-5,6,7,8-tetrahydroquinolin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol;(6-(6-(8-amino-8-propyl-5,6,7,8-tetrahydroquinolin-2-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol;(6-(6-(6-(3-aminooxetan-3-yl)pyridin-2-yl)-4-(2-methoxyethoxy)-1H-indazol-1-yl)pyridin-2-yl)methanol;(S)-(6-(6-(6-(1-aminobutyl)pyridin-2-yl)-4-(2-(methylsulfonyl)ethoxy)-1H-indazol-1-yl)pyridin-2-yl)methanol;(S)-(6-(6-(6-(1-aminobutyl)pyridin-2-yl)-4-((3,3-difluorocyclobutyl)methoxy)-1H-indazol-1-yl)pyridin-2-yl)methanol;and(S)-(6-(6-(6-(1-aminobutyl)pyridin-2-yl)-4-(1-methylpiperidin-4-yl)-1H-indazol-1-yl)pyridin-2-yl)methanol.

In any aspect or embodiment described herein, the PTM is represented byFormula PTM-X (i.e., Formulas PTM-Xa, PTM-Xb, PTM-Xc, PTM-Xd, PTM-Xe,PTM-Xf, and/or PTM-Xg, which correspond to Formula (I), the first andsecond structure of paragraph [0042] and the first and second structureof paragraph [0046] of U.S. Patent Application Publication No.2015/0011532 A1, the structure of paragraph [0046] of U.S. PatentApplication Publication No. 2015/0045347 A1, and Formula (I) and thestructure of paragraph [0045] of U.S. Patent Application Publication No.2016/0083375 A1, which is incorporated herein in its entirety for allpurposes):

wherein:

-   -   A of PTM-X is

or A of PTM-X is a triazole optionally substituted by 0-2 R

-   -   X of PTM-X is N or C—R⁷;    -   R of PTM-X is hydrogen, R¹, halogen, cyano, nitro, —OR¹,        —C(═O)—R¹, —C(═O)O—R¹, —C(═O)NR¹¹R¹, —S(═O)₂—R¹, —NR¹¹C(═O)—R¹,        —NR¹¹C(═O)NR¹¹R¹¹, —NR¹¹C(═O)NR¹R¹, —NR¹C(═O)O—R¹, NR¹¹S(═O)₂R¹,        —NR¹¹R¹¹, or NR¹¹R¹;    -   R¹ of PTM-X is C₁₋₆ alkyl substituted with 0-4 R^(1a), C₁₋₆        haloalkyl, C₂₋₆ alkenyl substituted with 0-3 R^(1a), C₂₋₆        alkynyl substituted with 0-3 R^(1a), C₃₋₁₀ cycloalkyl        substituted with 0-3 R^(1a), C₆₋₁₀ aryl substituted with 0-3        R^(1a), a 5-10 membered heterocycle containing 1-4 heteroatoms        selected from N, O, and S, substituted with 0-3 R^(1a), or a        5-10 membered heteroaryl containing 1-4 heteroatoms selected        from N, O, and S, substituted with 0-3 R^(1a);    -   R^(1a) of PTM-X is hydrogen, ═O, F, Cl, Br, OCF₃, CN, NO₂,        —(CH₂)_(r)OR^(b), —(CH₂)_(r)SR^(b), (CH₂)_(r)C(O)R^(b),        —(CH₂)_(r)C(O)OR^(b), —(CH₂)_(r)OC(O)R^(b), —(CH₂)_(r)NR¹¹R¹¹,        (CH₂)_(r)C(O)NR¹¹R¹¹, —(CH₂)_(r)NR^(b)C(O)R,        —(CH₂)_(r)NR^(b)C(O)OR^(c), NR^(b)C(O)NR¹¹R¹¹, S(O)_(p)NR¹¹R¹¹,        NR^(b)S(O)_(p)R^(c), —S(O)R^(c), —S(O)₂R^(c), C₁₋₆ alkyl        substituted with 0-2 R^(a), C₁₋₆ haloalkyl, —(CH₂)_(r)-3-14        membered carbocycle substituted with 0-3 R^(a), or        —(CH₂)_(r)-5-7 membered heterocycle or heteroaryl, each        comprising carbon atoms and 1-4 heteroatoms selected from N, O,        and S(O)_(p) substituted with 0-3 R^(a);    -   R² of PTM-X is C₆₋₁₀ aryl substituted with 0-4 R^(2a), a 5-10        membered heterocycle containing 1-4 heteroatoms selected from N,        O, and S, substituted with 1-4 R^(2a), or a 5-10 membered        heteroaryl containing 1-4 heteroatoms selected from N, O, and S,        substituted with 0-4 R^(2a);    -   R^(2a) of PTM-X at each occurrence is independently selected        from hydrogen, ═O, halo, OCF₃, CN, NO₂, —(CH₂)_(r)OR^(b),        —(CH₂)_(r)SR^(b), —(CH₂)_(r)C(O)R^(b), —(CH₂)_(r)C(O)OR^(b),        (CH₂)_(r)OC(O)R^(b), —(CH₂)_(r)NR¹¹R¹¹, —(CH₂)_(r)C(O)NR¹¹R¹¹,        —(CH₂)_(r)NR^(b)C(O)R^(c), (CH₂)_(r)NR^(b)C(O)OR^(c),        —NR^(b)C(O)NR¹⁰R¹¹, —S(O)_(p)NR¹¹R¹¹, —NR^(b)S(O)_(p)R^(c),        —S(O)R, —S(O)₂R^(c), C₁₋₆ alkyl substituted with 0-2 R^(a), C₁₋₆        haloalkyl, —(CH₂)_(r)-3-14 membered carbocycle substituted with        0-1 R^(a), or —(CH₂)_(r)-5-7 membered heterocycle or heteroaryl,        each comprising carbon atoms and 1-4 heteroatoms selected from        N, O, and S(O)_(v) substituted with 0-2 R^(a);    -   R³ of PTM-X is C₁₋₆alkyl substituted with 0-3 R^(3a), C₁₋₆        haloalkyl, C₂₋₆ alkenyl substituted with 0-3 R^(3a), C₂₋₆        alkynyl substituted with 0-3 R^(3a), C₃₋₁₀ cycloalkyl        substituted with 0-3 R^(3a), C₆₋₁₀ aryl substituted with 0-3        R^(3a), a 5-10 membered heterocyclyl containing 1-4 heteroatoms        selected from N, O, and S, substituted with 0-3 R^(3a) or a 5-10        membered heteroaryl containing 1-4 heteroatoms selected from N,        O, and S, substituted with 0-3 R^(3a);    -   R^(3a) of PTM-X is hydrogen, ═O, F, Cl, Br, OCF₃, CN, NO₂,        —(CH₂)_(r)OR^(b), —(CH₂)_(r)SR^(b), (CH₂)_(r)C(O)R^(b),        —(CH₂)_(r)C(O)OR^(b), —(CH₂)_(r)OC(O)R^(b), —(CH₂)_(r)NR¹¹R¹¹,        (CH₂)_(r)C(O)NR¹¹R¹¹, —(CH₂)_(r)NR^(b)C(O)R^(c),        —(CH₂)_(r)NR^(b)C(O)OR^(c), NR^(b)C(O)NR^(11R)1,        —S(O)_(p)NR¹¹R¹¹, NR^(b)S(O)_(p)R^(c), —S(O)R^(c), —S(O)₂R^(c),        C₁₋₆ alkyl substituted with 0-2 R^(a), C₁₋₆haloalkyl,        —(CH₂)_(r)-3-14 membered carbocycle substituted with 0-1 R^(a),        or —(CH₂)_(r)-5-7 membered heterocycle or heteroaryl, each        comprising carbon atoms and 1-4 heteroatoms selected from N, O,        and S(O)_(p) substituted with 0-1 R^(a);    -   R⁴ and R⁵ of PTM-X are independently selected from hydrogen,        C₁₋₄ alkyl substituted with 0-1 R^(f), (CH₂)-phenyl substituted        with 0-3 R^(d), and a —(CH₂)-5-7 membered heterocycle comprising        carbon atoms and 1-4 heteroatoms selected from N, O, and        S(O)_(p);    -   R⁶ and R⁷ of PTM-X are independently at each occurrence is        selected from hydrogen, ═O, F, Cl, Br, OCF₃, CN, NO₂,        —(CH₂)_(r)OR^(b), —(CH₂)_(r)SR^(b), —(CH₂)_(r)C(O)R^(b),        —(CH₂)_(r)C(O)OR^(b), —(CH₂)_(r)OC(O)R^(b), —(CH₂)_(r)NR¹¹R¹¹,        (CH₂)_(r)C(O)NR¹¹R¹¹, —(CH₂)_(r)NR^(b)C(O)R^(C),        (CH₂)_(r)NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹,        —NR^(b)S(O)_(p)R^(c), —S(O)R, —S(O)₂R^(c), C₁₋₆alkyl substituted        with 0-2 R^(a), C₁₋₆haloalkyl, —(CH₂)_(r)-3-14 membered        carbocycle substituted with 0-3 R^(a), or —(CH₂)_(r)-5-7        membered heterocycle or heteroaryl, each comprising carbon atoms        and 1-4 heteroatoms selected from N, O, and S(O)_(p) substituted        with 0-3 R^(a), provided R⁶ and R⁷ are not both hydrogen;    -   R¹¹ of PTM-X at each occurrence is independently hydrogen,        R^(e), C₁₋₄ alkyl substituted with 0-1 R^(f), CH₂-phenyl        substituted with 0-3 R^(d), or —(CH₂)-5-7 membered heterocycle        or heteroaryl, each comprising carbon atoms and 1-4 heteroatoms        selected from N, O, and S(O)_(p) substituted with 0-3 R^(d); or        R¹¹ and along with another R¹¹, R¹, or R² on the same nitrogen        atom may join to form an optionally substituted heterocycle;    -   R^(a) of PTM-X is hydrogen, F, Cl, Br, OCF₃, CF₃, CHF₂, CN, NO₂,        —(CH₂)_(r)OR^(b), (CH₂)_(r)SR^(b), —(CH₂)_(r)C(O)R^(b),        —(CH₂)_(r)C(O)OR^(b), —(CH₂)_(r)OC(O)R^(b), —(CH₂)_(r)NR¹¹R¹¹,        —(CH₂)_(r)C(O)NR¹¹R¹¹, —(CH₂)_(r)NR^(b)C(O)R^(c),        —(CH₂)_(r)NR^(b)C(O)OR^(c), NR^(b)C(O)NR¹⁰R¹¹, —S(O)_(p)NR¹¹R¹¹,        —NR^(b)S(O)_(p)R^(c), —S(O)R^(c), —S(O)₂R^(c), C₁₋₆ alkyl        substituted with 0-1 R^(f), C₁₋₆ haloalkyl, —(CH₂)_(r)-3-14        membered carbocycle, or —(CH₂)_(r)-5-7 membered heterocycle or        heteroaryl, each comprising carbon atoms and 1-4 heteroatoms        selected from N, O, and S(O)_(p); or two R^(a) on adjacent or        the same carbon atom form a cyclic acetal of the formula        —O—(CH₂)_(n)—O—, or —O—CF₂—O—, wherein n is selected from 1 or        2;    -   R^(b) of PTM-X is hydrogen, R^(e) of PTM-X, C₁₋₆ alkyl        substituted with 0-2 R^(d), C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl        substituted with 0-2 R^(d), or (CH₂)_(r)-phenyl substituted with        0-3 R^(d); Re is C₁₋₆ alkyl substituted with 0-1 R^(f), C₃₋₆        cycloalkyl, or (CH₂)_(r)-phenyl substituted with 0-3 R^(f);    -   R^(c) of PTM-X is C₁₋₆alkyl, C₃₋₆cycloalkyl, or (CH₂)_(r)-phenyl        substituted with 0-3 R^(f);    -   R^(d) of PTM-X is hydrogen, F, Cl, Br, OCF₃, CF₃, CN, NO₂,        —OR^(e), —(CH₂)_(r)C(O)R^(e), —NR^(e)R^(e), —NR^(e)C(O)OR^(c),        C₁₋₆ alkyl, or (CH₂)_(r)-phenyl substituted with 0-3 R^(f);    -   R^(e) of PTM-X is selected from hydrogen, C₁₋₆ alkyl, C₃₋₆        cycloalkyl, and (CH₂)_(r)-phenyl substituted with 0-3 R^(f);    -   R^(f) of PTM-X is hydrogen, halo, NH₂, OH, or O(C₁₋₆alkyl);    -   p of PTM-X is 0, 1, or 2;    -   r of PTM-X is 0, 1, 2, 3, or 4;    -   m of PTM-X is 0, 1, or 2; and    -   the PTM-X is covalently joined to a ULM, a chemical linker group        (L), a CLM, an ILM, a VLM, MLM, a ULM′, a CLM′, a ILM′, a VLM′,        a MLM′, or combination thereof.

In any aspect or embodiment described herein, the PTM-X is covalentlyjoined to a ULM, a chemical linker group (L), a CLM, an ILM, a VLM, MLM,a ULM′, a CLM′, a ILM′, a VLM′, a MLM′, or combination thereof via an Rgroup (e.g., R¹, R^(1a), R², R^(2a), R³, R^(3a), R⁴, R⁵, R⁶, R⁷, R¹¹,R^(a), R^(b), R^(c), R_(d), R^(e), or R^(f)).

In any aspect or embodiment described herein, R² of PTM-X is phenyl,pyridyl, pyrimidinyl, naphthyl, indolinyl, benzothiazolyl,pyrazolopyridinyl, benzoisothiazolyl, triazolopyridinyl,imidazopyridinyl, benzooxazolyl, triazolopyridinyl, imidazopyridinyl,pyridopyrazinyl, quinazolinyl, pyridopyrazinyl, benzooxadiazolyl,benzothiadiazolyl, benzoimidazolyl, triazolopyridinyl,imdazopyridazinyl, pyridopyrazinyl, naphthyridinyl, quinoxalinyl,phthalazinyl, quinolinyl, indolyl, benzothiazolyl, benzodioxolyl,benzothienyl, isoquinolinyl, benzopyranyl, indolizinyl, benzofuranyl,chromonyl, coumarinyl, benzopyranyl, cinnolinyl, pyrrolopyridyl,furopyridyl, isoindolyl, or quinazolinyl, each group substituted by 1-4groups selected from R^(2a).

In any aspect or embodiment described herein, R² of PTM-X is selectedfrom

wherein each group is substituted by 0-4 R^(2a).

In any aspect or embodiment described herein, R² of PTM-X is selectedfrom

In any aspect or embodiment described herein, R¹ of PTM-X is selectedfrom

In any aspect or embodiment described herein, R of PTM-X is selectedfrom —C(O)NH₂, —C(O)OC₁-6alkyl, —C(O)NH(C₁₋₆alkyl), —C(O)N(C₁₋₆alkyl)₂,

wherein each group substituted by 0-3 R^(1a)

In any aspect or embodiment described herein, R^(1a) of PTM-X isselected from

In any aspect or embodiment described herein, the PTM is represented byFormula PTM-XI (i.e., Formulas PTM-XIa, PTM-XIb and/or PTM-XIc whichcorrespond to Formulas I and II of International Patent ApplicationPublication WO 2016/053769 A1, Formulas I and II of International PatentApplication Publication WO 2016/053770, Formulas I and II ofInternational Patent Application Publication WO 2016/053771 A1 andFormula I of International Patent Application Publication WO 2016/053772A1, which are incorporated herein in their entirety for all purposes):

wherein:

-   -   X of PTM-XI is NH or O;    -   b of PTM-XI is 0 or 1;    -   n of PTM-XI is 0, 1, 2, 3 or 4;    -   R₁ and R₂ of PTM-XI are independently H, (C₁-C₄)alkyl and        heterocyclyl, or R₁ and R₂ can be taken together with the        nitrogen to which they are attached to form a monocyclic or        bicyclic (fused, bridged or spirocyclic) heterocycle containing        3-8 carbon atoms optionally containing, in addition to the        nitrogen, one or two additional heteroatoms selected from N, O        and S, said alkyl and heterocycle are optionally substituted        with one or more substituents selected from R_(a);    -   R³ of PTM-XI is (C₁-C₄)alkyl wherein two adjacent alkyl groups        can join together and form a bridged moiety of 3-6 carbon atoms;    -   R₄ of PTM-XI is absent, halo or O_(b)(C₁-C₄)alkyl;    -   R₅ of PTM-XI is selected from halo, CN, O(C₁-C₄)alkyl, C₁-C₄        alkyl and C₂-C₄ alkenyl which are optionally substituted with        one or more substituents selected from R_(b) or R₅ is aryl or        heteroaryl each optionally substituted with one or more        substitutents selected from R^(b);    -   R₆ of PTM-XI is absent, halo, or O(C₁-C₄)alkyl;    -   R_(a) of PTM-XI is halo, oxo, OH, O_(b)(C₁-C₄)alkyl,        C(O)O_(b)(C₁-C₆)alkyl, (C═O)_(b)heterocyclyl, CF₃, SO₂H,        SO₂(C₁-C₄)alkyl, C(O)C₁-C₄alkyl, or heterocyclyl, wherein said        alkyl can come together with another alkyl to form a bridged        moiety and said alkyl and heterocyclyl are optionally        substituted with one or more substituents independently selected        from F and (C₁-C₄)alkyl; and    -   R_(b) of PTM-XI is independently selected from OH, halo, CHF₂,        CF₃, COOH, SO₂(C₁-C₄)alkyl, C(O)C₁-C₄alkyl, (C═O)NH₂,        O_(b)(C₁-C₄)alkyl, aryl, heterocyclyl, CN, C(O)N(R^(c))₂,        N(R^(c))₂, wherein the R^(C) and alkyl are optionally        substituted with OH, O(C₁-C₄)alkyl and heterocyclyl; and    -   R^(c) of PTM-XI is independently selected from H,        SO₂(C₁-C₄)alkyl, or C₁-C₄ alkyl;    -   the PTM-XI is covalently joined to a ULM, a chemical linker        group (L), a CLM, an ILM, a VLM, MLM, a ULM′, a CLM′, a ILM′, a        VLM′, a MLM′, or combination thereof.

In any aspect or embodiment described herein, the PTM-XI is covalentlyjoined to a ULM, a chemical linker group (L), a CLM, an ILM, a VLM, MLM,a ULM′, a CLM′, a ILM′, a VLM′, a MLM′, or combination thereof via an Rgroup (e.g., R₁, R₂, R₃, R₄, R₅, R₆, R_(a), R_(b), or R_(c)).

In any aspect or embodiment described herein, the PTM of PTM-XIbcomprises at least one of:

-   -   X of PTM-XI is NH or O;    -   b of PTM-XI is 0 or 1;    -   R₁ and R₂ of PTM-XI are independently H, (C₁-C₄)alkyl and        tetrahydopyranyl; or R₁ and R2 can be taken together with the        nitrogen to which they are attached to form morpholinyl,        azetidinyl, piperazinyl, pyrrolidinyl, piperidinyl,        oxaazaspirooxtyl, oxaazapiroheptanyl and thiomorpholinyl, said        alkyl, morpholinyl, azetidinyl, piperazinyl, pyrrolidinyl,        piperidinyl, oxaazaspirooxtyl, oxaazapiroheptanyl and        thiomorpholinyl are optionally substituted with one or more        substituents independently selected from R_(a);    -   R₅ of PTM-XI is selected from C₁-C₄ alkyl and C₂-C₄ alkenyl        which are optionally substituted with one or more substituents        selected from R_(b);    -   R₆ of PTM-XI is absent, F or methyl;    -   R_(a) of PTM-XI is F, oxo, OH, O_(b)(C₁-C₄)alkyl, CF₃,        SO₂(C₁-C₄)alkyl, oxetanyl, pyrazolyl, tetrahydropyranyl and        thiophenyl, said oxetanyl, pyrazolyl, tetrahydropyranyl and        thiophenyl optionally substituted with one or more substituents        independently selected from F, and (C₁-C₄)alkyl; and    -   R_(b) of PTM-XI is independently selected from OH, F,        O_(b)(C₁-C₄)alkyl, and CN.

In any aspect or embodiment, the PTM of PTM-XI is selected from:(trans)-N1-(6,7-dimethylquinazolin-4-yl)-N4,N4-dimethylcyclohexane-1,4-diamine(PTM-XI-1);trans-N,N-dimethyl-N′-(6-methylquinazolin-4-yl)cyclohexane-1,4-diamine(PTM-XI-2);6-methyl-N-(trans-4-morpholin-4-ylcyclohexyl)quinazolin-4-amine(PTM-XI-3);N-(trans-4-morpholin-4-ylcyclohexyl)-6-(trifluoromethyl)quinazolin-4-amine(PTM-XI-4);7-fluoro-6-methyl-N-(trans-4-morpholin-4-ylcyclohexyl)quinazolin-4-amine(PTM-XI-5);trans-N,N-dimethyl-N′-[6-(trifluoromethyl)quinazolin-4-yl]cyclohexane-1,4-diamine(PTM-XI-6);4-((trans)-4-((6-methylquinazolin-4-yl)oxy)cyclohexyl)morpholine(PTM-XI-7);6-methyl-N-((/R,4R)-4-(3-(methylsulfonyl)azetidin-1-yl)cyclohexyl)quinazolin-4-amine(PTM-XI-8);N-[cis-4-(3-fluoroazetidin-1-yl)cyclohexyl]-6-methylquinazolin-4-amine(PTM-XI-9);N-[trans-4-(3-fluoroazetidin-1-yl)cyclohexyl]-6-methylquinazolin-4-amine(PTM-XI-10);4-{cis-4-[(6-methylquinazolin-4-yl)amino]cyclohexyllpiperazin-2-one(PTM-XI-11);4-{trans-4-[(6-methylquinazolin-4-yl)amino]cyclohexyl}piperazin-2-one(PTM-XI-12);1-{trans-4-[(6-methylquinazolin-4-yl)amino]cyclohexyl}azetidin-3-ol(PTM-XI-13);1-{cis-4-[(6-methylquinazolin-4-yl)amino]cyclohexyl}azetidin-3-ol(PTM-XI-14);N-[trans-4-(3,3-difluoropyrrolidin-1-yl)cyclohexyl]-6-methylquinazolin-4-amine(PTM-XI-15);6-methyl-N-[trans-4-(2-oxa-6-azaspiro[3.4]oct-6-yl)cyclohexyl]quinazolin-4-amine(PTM-XI-16);6-methyl-N-{cis-4-[3-(methylsulfonyl)azetidin-1-yl]cyclohexyl}quinazolin-4-amine(PTM-XI-17);6-methyl-N-{4-[4-(trifluoromethyl)piperidin-1-yl]cyclohexyl}quinazolin-4-amine(PTM-XI-18);6-methyl-N-{4-[4-(trifluoromethyl)piperidin-1-yl]cyclohexyl}quinazolin-4-amine(PTM-XI-19);6-methyl-N-{4-[3-(trifluoromethyl)piperidin-1-yl]cyclohexyl}quinazolin-4-amine(PTM-XI-20);6-methyl-N-{4-[2-(trifluoromethyl)piperidin-1-yl]cyclohexyl}quinazolin-4-amine(PTM-XI-21);6-methyl-N-{4-[2-(trifluoromethyl)piperidin-1-yl]cyclohexyl}quinazolin-4-amine(PTM-XI-22);6-methyl-N-{4-[3-(trifluoromethyl)piperidin-1-yl]cyclohexyllquinazolin-4-amine (2-16);(trans)-N1-(6-methylquinazolin-4-yl)-N4-(tetrahydro-2H-pyran-4-yl)cyclohexane-1,4-diamine(PTM-XI-23);trans-N-(6-methylquinazolin-4-yl)-N′-(tetrahydro-2H-pyran-4-ylmethyl)cyclohexane-1,4-diamine(PTM-XI-24);trans-N-[(4S)-2,2-dimethyltetrahydro-2H-pyran-4-yl]-N′-(6-methylquinazolin-4-yl)cyclohexane-1,4-diamine(PTM-XI-25);trans-N-(6-methylquinazolin-4-yl)-N′-(thiophen-2-ylmethyl)cyclohexane-1,4-diamine(PTM-XI-26);trans-N-[(1S)-1-cyclopropylethyl]-N′-(6-methylquinazolin-4-yl)cyclohexane-1,4-diamine(PTM-XI-27);trans-N-(6-methylquinazolin-4-yl)-N-[(1S)-3,3,3-trifluoro-lmethylpropyl]cyclohexane-1,4-diamine(PTM-XI-28);(3S)-2-methyl-3-({trans-4-[(6-methylquinazolin-4-yl)amino]cyclohexyllamino)butan-2-ol (PTM-XI-29);trans-N-(1-methylethyl)-N′-(6-methylquinazolin-4-yl)cyclohexane-1,4-diamine(PTM-XI-30);trans-N-(cyclopropylmethyl)-N′-(6-methylquinazolin-4-yl)cyclohexane-1,4-diamine(PTM-XI-31);trans-N-[(1-methyl-1H-pyrazol-5-yl)methyl]-N′-(6-methylquinazolin-4-yl)cyclohexane-1,4-diamine(PTM-XI-32); trans-N-[(3-methyloxetan-3-yl)methy1]—N′-(6-methylquinazolin-4-yl)cyclohexane-1,4-diamine (PTM-XI-33);trans-N-(6-methylquinazolin-4-yl)-N′-(3,3,3-trifluoropropyl)cyclohexane-1,4-diamine(PTM-XI-34);trans-N-(2,2-dimethylpropyl)-N′-(6-methylquinazolin-4-yl)cyclohexane-1,4-diamine(PTM-XI-35); trans-N-[(1S)-2,2-difluoro-1-methylethy1]—N′-(6-methylquinazolin-4-yl)cyclohexane-1,4-diamine (PTM-XI-36);trans-N-[(1S)-1-methyl-2-(methylsulfonyl)ethyl]-N′-(6-methylquinazolin-4-yl)cyclohexane-1,4-diamine(PTM-XI-37);(trans)-N1-(6-((E)-2-cyclopropylvinyl)quinazolin-4-yl)-N4,N4-dimethylcyclohexane-1,4diamine(PTM-XI-38);N′-(6-ethenylquinazolin-4-yl)-N,N-dimethylcyclohexane-1,4-diamine(PTM-XI-39);trans-N′-{6-[(1E)-3-methoxyprop-1-en-1-yl]quinazolin-4-yl}-N,N-dimethylcyclohexane-1,4-diamine(PTM-XI-40);6-ethyl-N-(trans-4-morpholin-4-ylcyclohexyl)quinazolin-4-amine(PTM-XI-41);4-(4-(((trans)-4-morpholinocyclohexyl)amino)quinazolin-6-yl)butanenitrile(PTM-XI-42);(trans)-N1-(6-ethylquinazolin-4-yl)-N4,N4-dimethylcyclohexane-1,4-diamine(PTM-XI-43);N,N-dimethyl-N′-[6-(1-methylethyl)quinazolin-4-yl]cyclohexane-1,4-diamine(PTM-XI-44);6-butyl-N-(trans-4-morpholin-4-ylcyclohexyl)quinazolin-4-amine(PTM-XI-45);N-(trans-4-morpholin-4-ylcyclohexyl)-6-propylquinazolin-4-amine(PTM-XI-46);2-(4-(((trans)-4-(dimethylamino)cyclohexyl)amino)quinazolin-6-yl)ethan-1-ol(PTM-XI-47);3-{4-[(trans-4-morpholin-4-ylcyclohexyl)amino]quinazolin-6-yl}propan-1-ol(PTM-XI-48);4-{4-[(trans-4-morpholin-4-ylcyclohexyl)amino]quinazolin-6-yl}butan-1-ol(PTM-XI-49);1-(4-{[trans-4-(dimethylamino)cyclohexyl]aminolquinazolin-6-yl)ethanol(PTM-XI-50);4-((trans)-4-[(6-methylquinazolin-4-yl)amino)cyclohexyl)thiomorpholine-1,1-dioxide(PTM-XI-51);N-((trans)-4-(2-oxa-6-azaspiro[3.3]heptan-6-yl)cyclohexyl)-6-methylquinazolin-4-amine(PTM-XI-52);4-(4-(((trans)-4-Morpholinocyclohexyl)amino)quinazolin-6-yl)butan-2-ol(PTM-XI-53);(4-(((trans)-4-(dimethylamino)cyclohexyl)amino)quinazolin-6-yl)methanol(PTM-XI-54).

In any aspect or embodiment described herein, the PTM is represented byFormula PTM-XII (i.e., Formulas PTM-XIIa, PTM-XIIb, PTM-XIIc, PTM-XIId,PTM-XIIe, and/or PTM-XIIf, which correspond to Formulas I and II ofInternational Patent Application Publication WO 2016/144844 A1, FormulaI of International Patent Application Publication WO 2016/144846 A1,Formula I of International Patent Application Publication WO 2016/144847A1, Formula I of International Patent Application Publication WO2016/144848 A1, and Formula I of International Patent ApplicationPublication WO 2016/144849 A1, which are incorporated herein in theirentirety for all purposes):

wherein:

-   -   B of PTM-XII is CH, N or S; D of PTM-XII is CH or N; E of        PTM-XII is CH or N; F of PTM-XII is CH or N; G of PTM-XII is CH        or N; and J of PTM-XII is C or N, wherein when B is S then D is        CH, E is N, F is CH, G is N and J is C;    -   X of PTM-XII is O, S, CH₂ or N;    -   m of PTM-XII is 0 or 1;    -   n of PTM-XII is 0, 1, 2, 3 or 4;    -   Ring A of PTM-XII is aryl, heterocyclyl, pyridinyl, pyrazolyl,        thiophenyl, furanyl or phenyl;    -   R₁ of PTM-XII is independently selected from (C₁-C₄)alkyl,        (C₃-C₆)cycloalkyl, heterocyclyl, CF₃, CHF₂, CN, halo,        pyrimidine, piperidine and phenyl, each optionally substituted        with (C₁-C₄)alkyl, OH, CH₃, OCH₃, halo, O(C₁-C₄)alkyl,        methyl-piperidine, S(O)₂R_(c), C(O)N(R^(b))₂, or        C(O)O(C₁-C₄)alkyl;    -   R₂ of PTM-XII is absent or H and R₃ is independently selected        from: (C₁-C₄)alkyl, (C₁-C₆)alkyl, (C₃-C₈)cycloalkyl,        heterocyclyl, pyranyl, cyclopentyl, cyclohexyl, cycloheptyl,        thiopyranyl, pyrazolyl, piperidinyl, morpholinyl, piperazinyl,        each optionally substituted with one or more substituents        independently selected from halo, OH, oxo, N(R_(b))₂,        oxopyrrolidinyl, or morpholinyl, or R₂ and R₃ can be taken        together with the nitrogen to which they are attached to form a        heterocyclyl, piperazine or morpholine, each optionally        substituted with one or more substituents selected from oxo and        R_(a);    -   R₄ of PTM-XII is independently H or methyl;    -   R_(a) of PTM-XIIa-f is independently selected from (C₁-C₄)alkyl,        (C₃-C₆)cycloalkyl, cyclopropyl, CF₃, F, CHF₂, OH, halo and NH₂,        said alkyl optionally substituted with (C₃-C₆)cycloalkyl and        CF₃; and    -   R_(b) of PTM-XII is independently selected from H and        (C₁-C₄)alkyl;    -   R_(c) of PTM-XII is methyl; and    -   the PTM-XII is covalently joined to a ULM, a chemical linker        group (L), a CLM, an ILM, a VLM, MLM, a ULM′, a CLM′, a ILM′, a        VLM′, a MLM′, or combination thereof.

In any aspect or embodiment described herein, the PTM-XII is covalentlyjoined to a ULM, a chemical linker group (L), a CLM, an ILM, a VLM, MLM,a ULM′, a CLM′, a ILM′, a VLM′, a MLM′, or combination thereof via an Rgroup (e.g., R¹, R², R³, R⁴, R^(a), R^(b), R^(c), or R^(d)).

In any aspect or embodiment described herein, at least one of:

of PTM-XIIa is

and

-   -   X of PTM-XIIa is O, CH₂ or N.

In any aspect or embodiment described herein, at least one of:

of PTM-XIIa is

and

X of PTM-XIIa is O, S, CH₂ or N.

In any aspect or embodiment described herein, the PTM is represented byFormula PTM-XIII (i.e., Formulas PTM-XIIIa, PTM-XIIIb, PTM-XIIIc, and/orPTM-XIIId, which correspond to Formulas I, IA, IB, and IC of U.S PatentApplication Publication No. 2016/0326151 A1, which is incorporatedherein in its entirety for all purposes, and/or PTM-XIIIe, PTM-XIIIf,and/or PTM-XIIIg, which corresponds to Formula(I) of InternationalPatent Application Publication No. WO 2016/174183, which is incorporatedherein in its entirety for all purposes, PTM-XIIIi, and/or PTM-XIIIj):

wherein:

-   -   Ring Z₁ of PTM-XIII is an optionally substituted heteroaryl;    -   Ring Z₂ of PTM-XIII is an optionally substituted        heterocycloalkyl, optionally substituted heteroaryl or a direct        bond;    -   R₁ of PTM-XIII is optionally substituted alkyl, optionally        substituted hydroxy alkyl, cyano, —NR_(a)R_(b), optionally        substituted cycloalkyl, optionally substituted aryl or        optionally substituted heterocyclyl; wherein the substituent, at        each occurrence, independently is alkyl, alkoxy, halogen,        hydroxyl, hydroxyalkyl, amino, aminoalkyl, nitro, cyano,        haloalkyl, haloalkoxy, —OCO—CH₂—O-alkyl, —OP(O)(O-alkyl)₂ or        —CH₂—OP(O)(O-alkyl)₂;    -   R₂ of PTM-XIII, at each occurrence, independently is an        optionally substituted group selected from alkyl, cycloalkyl, or        cycloheteroalkyl; wherein the substituent, at each occurrence,        is independently halogen, alkoxy, hydroxyl, hydroxyalkyl,        haloalkyl or haloalkoxy;    -   R_(2a) of PTM-XIIIa-g is an H or optionally substituted alkyl        (e.g., optionally substituted C1-C4 alkyl);    -   R₃ of PTM-XIII, at each occurrence, independently is hydrogen,        halogen, alkyl, haloalkyl, haloalkoxy, alkoxy, —NR_(a)R_(b),        hydroxyl or hydroxyalkyl;    -   R₄ of PTM-XIII at each occurrence is independently is halogen,        cyano, an unsubstituted or a singly or multiply, identically or        differently substituted C1-C5-alkyl or an unsubstituted or a        singly or multiply, identically or differently substituted        C3-C6-cycloalkyl (e.g., the substituents of the alkyl or        cycloalkyl may be selected from the group of halogen and        hydroxyl);    -   R₅ of PTM-XIII at each occurrence is independently is hydrogen,        halogen or an unsubstituted or poly-halogen-substituted        C1-C5-alkyl;    -   R₆ of PTM-XIII at each occurrence is independently optionally        substituted C1-C6-alkyl (e.g., C1-C6-alkyl radical        unsubstituted, monobustituted or polysubstituted identically or        differently by halogen, hydroxyl, an unsubstituted or mono- or        poly-halogen-substituted C3-C6-cycloalkyl, or an R⁹, R¹⁰SO₂,        R¹⁰SO or R¹¹O radical, or a group selected from:

wherein * represents the bonding site of the group to the rest of themolecule);

-   -   R₇ and R₈ of PTM-XIII at each occurrence is independently        selected from hydrogen or C1-C6-alkyl (e.g., both may be H or a        C1-C6 alkyl, including the same C1-C6 alkyl);    -   R₉ of PTM-XIII is an unsubstituted or mono- or        di-methyl-substituted monocyclic saturated heterocycle having 4        to 6 ring atoms, which contains a heteroatom or a heterogroup        from the group of O, S, SO and SO₂;    -   R₁₀ of PTM-XIII is a C1-C6-alkyl, where the C1-C5-alkyl radical        is unsubstituted or mono- or polysubstituted identically or        differently by halogen, hydroxyl or C3-C5-cycloalkyl; or R₁₀ is        C3-C6-cycloalkyl    -   R₁₁ of PTM-XIII is an optionally substituted C1-C6-alkyl (e.g.,        a C1-C6-alkyl radical is unsubstituted or mono- or        polysubstituted identically or differently by, e.g., halogen);    -   R_(a) of PTM-XIII is hydrogen or alkyl;    -   R_(b) of PTM-XIII is hydrogen, alkyl, acyl, hydroxyalkyl,        —SO₂-alkyl or optionally substituted cycloalkyl;    -   R₁₂ of PTM-XIII is optionally substituted C1-C5 alkyl,        optionally substituted methyl, optionally substituted ethyl,        optionally substituted cyloalky, or

-   -   R¹³ of PTM-XIII is H or methyl;    -   R₁₄ of PTM-XIII is an optionally substituted linear or branched        alkyl (e.g., optionally substituted linear or branched C1-C8        alkyl), optionally substituted amide, carboxylic group,        optionally substituted cycloalkyl, optionally substituted        heterocycloalkyl, optionally substituted aryl (e.g., optionally        substituted C5-C7 aryl), optionally substituted heteroaryl        (e.g., optionally substituted C5-C7 heteroaryl), —SO₂-alkyl,        —SO₂H, —O-alkyl, —O-aryl, —O-heteroaryl, optionally substituted        urea group;    -   W and Y of PTM-XIII are selected from C and N with the proviso        that one is N and one is C;    -   X of PTM-XIII is CH or N;    -   “m” of PTM-XIII is 1 or 2;    -   “n” of PTM-XIII is 1 or 2; and    -   the PTM-XIII is covalently joined to a ULM, a chemical linker        group (L), a CLM, an ILM, a VLM, MLM, a ULM′, a CLM′, a ILM′, a        VLM′, a MLM′, or combination thereof.

In any aspect or embodiment described herein, the PTM-XIII is covalentlyjoined to a ULM, a chemical linker group (L), a CLM, an ILM, a VLM, MLM,a ULM′, a CLM′, a ILM′, a VLM′, a MLM′, or combination thereof via an Rgroup (e.g., R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃,R₁₄, R_(a), R_(b), or R_(c)).

In any aspect or embodiment described herein, R14 is selected from:

In any aspect or embodiment described herein, Ring Z₁ of PTM-XIII is a5- or 6-membered optionally substituted heteroaryl.

In any aspect or embodiment described herein, Ring Z₁ of the PTM-XIII isselected from the group consisting of tetrazolyl, thienyl, triazolyl,pyrrolyl, pyridyl, pyranyl, pyrazinyl, pyridazinyl, pyrimidyl,imidazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, isothiazolyl,oxazolyl, furanyl and pyrazolyl.

In any aspect or embodiment described herein, Ring Z₂ of PTM-XIII is a5- or 6-membered heteroaryl selected from tetrazolyl, thienyl,triazolyl, pyrrolyl, pyridyl, pyranyl, pyrazinyl, pyridazinyl,pyrimidyl, imidazolyl, oxadiazolyl, thiadiazolyl, thiazolyl,isothiazolyl, oxazolyl, furanyl or pyrazolyl.

In any aspect or embodiment described herein, Ring Z₂ of PTM-XIII is a5- or 6-membered heterocycloalkyl selected from azetidinyl, oxetanyl,imidazolidinyl, pyrrolidinyl, oxazolidinyl, thiazolidinyl,pyrazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl,tetrahydropyranyl, morpholinyl, thiomorpholinyl or 1,4-dioxanyl.

In any aspect or embodiment described herein, the PTM of PTM-XIII isselected from the group consisting of:N-(2-methyl-6-(piperidin-1-yl)-2H-indazol-5-yl)-6-(1H-pyrazol-4-yl)picolinamide;N-(2-methyl-6-(piperidin-1-yl)-2H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide;N-(1-methyl-6-(piperidin-1-yl)-1H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide;N-(2-cyclopentyl-6-(piperidin-1-yl)-2H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide;N-(6-cyano-2-cyclopentyl-2H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide;N-(2-cyclopentyl-6-cyclopropyl-2H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide;N-(2-cyclopentyl-6-cyclopropyl-2H-indazol-5-yl)-6-(1H-pyrazol-4-yl)picolinamide;N-(2-cyclopentyl-6-morpholino-2H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide;6′-amino-N-(2-cyclopentyl-6-morpholino-2H-indazol-5-yl)-[2,3′-bipyridine]-6-carboxamide2,2,2-trifluoroacetate;N-(6-(3-fluorophenyl)-2-methyl-2H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide;N-(6-cyclohexyl-2-methyl-2H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamidehydrochloride;6′-fluoro-N-(2-methyl-6-(piperidin-1-yl)-2H-indazol-5-yl)-[2,3′-bipyridine]-6-carboxamidehydrochloride;N-(6-cyclohexyl-2-methyl-2H-indazol-5-yl)-6-(1H-pyrazol-4-yl)picolinamidehydrochloride;2′-fluoro-N-(2-methyl-6-(piperidin-1-yl)-2H-indazol-5-yl)-[2,3′-bipyridine]-6-carboxamide;2-(2-chloropyridin-4-yl)-N-(2-methyl-6-(piperidin-1-yl)-2H-indazol-5-yl)oxazole-4-carboxamidehydrochloride;N-(6-cyclopropyl-2-methyl-2H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamidehydrochloride;N-(1-cyclopentyl-6-cyclopropyl-1H-indazol-5-yl)-6-(1-methyl-1H-pyrazol-4-yl)picolinamide;N-(2-cyclopentyl-6-cyclopropyl-2H-indazol-5-yl)-6-(1-methyl-1H-pyrazol-4-yl)picolinamide;6-(1-methyl-1H-pyrazol-4-yl)-N-(2-methyl-6-(piperidin-1-yl)-2H-indazol-5-yl)picolinamide;N-(2-cyclopentyl-6-cyclopropyl-2H-indazol-5-yl)-2-(6-methoxypyridin-3-yl)oxazole-4-carboxamide;2-(6-methoxypyridin-3-yl)-N-(2-methyl-6-(piperidin-1-yl)-2H-indazol-5-yl)oxazole-4-carboxamide;N-(2-methyl-6-(piperidin-1-yl)-2H-indazol-5-yl)-2-(3-methylpyridin-4-yl)oxazole-4-carboxamide;6-bromo-N-(2-methyl-6-(piperidin-1-yl)-2H-indazol-5-yl)picolinamide;6-chloro-5-methyl-N-(2-methyl-6-(piperidin-1-yl)-2H-indazol-5-yl)picolinamideN-(2-methyl-6-(piperidin-1-yl)-2H-indazol-5-yl)-2-(6-methylpyridin-3-yl)oxazole-4-carboxamide;N-(2-cyclopentyl-6-cyclopropyl-2H-indazol-5-yl)-2-(2-methylpyridin-3-yl)oxazole-4-carboxamide;N-(2-cyclopentyl-6-cyclopropyl-2H-indazol-5-yl)-2-(3-methylpyridin-4-yl)oxazole-4-carboxamide;N-(2-cyclopentyl-6-cyclopropyl-2H-indazol-5-yl)-2-(6-methylpyridin-3-yl)oxazole-4-carboxamide;6′-amino-3-methyl-N-(2-methyl-6-(piperidin-1-yl)-2H-indazol-5-yl)-[2,3′-bipyridine]-6-carboxamidehydrochloride;5-methyl-6-(1-methyl-1H-pyrazol-4-yl)-N-(2-methyl-6-(piperidin-1-yl)-2H-indazol-5-yl)picolinamide;N-(1-cyclopropyl-6-(piperidin-1-yl)-1H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamidehydrochloride;2-(2-hydroxypyridin-3-yl)-N-(2-methyl-6-(piperidin-1-yl)-2H-indazol-5-yl)oxazole-4-carboxamide;(S)-6-(3-aminopyrrolidin-1-yl)-N-(2-methyl-6-(piperidin-1-yl)-2H-indazol-5-yl)picolinamide2,2,2-trifluoroacetate; 34.(S)-6-(1-(2-hydroxypropyl)-1H-pyrazol-4-yl)-N-(2-methyl-6-(piperidin-1-yl)-2H-indazol-5-yl)picolinamide;N-(1,6-dicyclopropyl-1H-indazol-5-yl)-2-(6-methoxypyridin-3-yl)oxazole-4-carboxamide;N-(1,6-dicyclopropyl-1H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamidehydrochloride;(S)—N-(6-cyclopropyl-1-methyl-1H-indazol-5-yl)-6-(3-hydroxypyrrolidin-1-yl)picolinamide;(R)-6-(3-hydroxypyrrolidin-1-yl)-N-(2-methyl-6-(piperidin-1-yl)-2H-indazol-5-yl)picolinamide;(S)-6-(3-hydroxypyrrolidin-1-yl)-N-(2-methyl-6-(piperidin-1-yl)-2H-indazol-5-yl)picolinamide;6-(3-hydroxypyrrolidin-1-yl)-N-(2-methyl-6-(piperidin-1-yl)-2H-indazol-5-yl)picolinamide;(S)-6-(3-aminopyrrolidin-1-yl)-N-(6-cyclopropyl-1-methyl-1H-indazol-5-yl)picolinamide;(R)-6-(3-aminopyrrolidin-1-yl)-N-(2-methyl-6-(piperidin-1-yl)-2H-indazol-5-yl)picolinamide;(R)-6-(1-(2-hydroxypropyl)-1H-pyrazol-4-yl)-N-(2-methyl-6-(piperidin-1-yl)-2H-indazol-5-yl)picolinamide;(S)-2-(3-aminopyrrolidin-1-yl)-N-(2-methyl-6-(piperidin-1-yl)-2H-indazol-5-yl)oxazole-4-carboxamide;N-(6-cyclopropyl-1-methyl-1H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide;(S)—N-(6-cyclopropyl-1-methyl-1H-indazol-5-yl)-6-(1-(2-hydroxypropyl)-1H-pyrazol-4-yl)picolinamide;(S)—N-(6-cyclopropyl-2-methyl-2H-indazol-5-yl)-6-(1-(2-hydroxypropyl)-1H-pyrazol-4-yl)picolinamide;(S)-6-(3-aminopyrrolidin-1-yl)-N-(6-cyclopropyl-2-methyl-2H-indazol-5-yl)picolinamide;(S)—N-(6-cyclopropyl-2-methyl-2H-indazol-5-yl)-6-(3-hydroxypyrrolidin-1-yl)picolinamide;(S)—N-(6-cyclopropyl-1-methyl-1H-indazol-5-yl)-2-(3-hydroxypyrrolidin-1-yl)oxazole-4-carboxamide;(S)-2-(3-aminopyrrolidin-1-yl)-N-(6-cyclopropyl-1-methyl-1H-indazol-5-yl)oxazole-4-carboxamide;(S)-2-(3-hydroxypyrrolidin-1-yl)-N-(2-methyl-6-(piperidin-1-yl)-2H-indazol-5-yl)oxazole-4-carboxamide;(S)—N-(6-cyclopropyl-1-methyl-1H-indazol-5-yl)-2-(1-(2-hydroxypropyl)-1H-pyrazol-4-yl)oxazole-4-carboxamide;(S)-2-(3-aminopyrrolidin-1-yl)-N-(6-cyclopropyl-2-methyl-2H-indazol-5-yl)oxazole-4-carboxamide;(S)—N-(6-cyclopropyl-2-methyl-2H-indazol-5-yl)-2-(3-hydroxypyrrolidin-1-yl)oxazole-4-carboxamide;(S)-6-(1-(2-hydroxypropyl)-1H-pyrazol-4-yl)-N-(2-methyl-6-(piperidin-1-yl)-2H-indazol-5-yl)picolinamide;6-((2-hydroxypropyl)amino)-N-(2-methyl-6-(piperidin-1-yl)-2H-indazol-5-yl)picolinamide;N-(6-(4-hydroxypiperidin-1-yl)-2-methyl-2H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide;N-(6-(azetidin-1-yl)-1-methyl-1H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide;N-(6-(azetidin-1-yl)-2-methyl-2H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide;N-(6-(3-hydroxyazetidin-1-yl)-2-methyl-2H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide;N-(1-methyl-6-(pyrrolidin-1-yl)-1H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide;N-(2-methyl-6-(pyrrolidin-1-yl)-2H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide;(S)—N-(6-(3-hydroxypyrrolidin-1-yl)-2-methyl-2H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide;(R)—N-(6-(3-hydroxypyrrolidin-1-yl)-2-methyl-2H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide;N-(2-methyl-6-(piperidin-1-yl)-2H-indazol-5-yl)-5-(2-methylpyridin-4-yl)furan-2-carboxamide;N-(6-(4-hydroxypiperidin-1-yl)-2-methyl-2H-indazol-5-yl)-5-(2-methylpyridin-4-yl)furan-2-carboxamide;N-(6-(3-hydroxypiperidin-1-yl)-2-methyl-2H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide;(R)—N-(6-(3-hydroxypiperidin-1-yl)-2-methyl-2H-indazol-5-yl)-5-(2-methylpyridin-4-yl)furan-2-carboxamide;N-(6-(3-hydroxypiperidin-1-yl)-2-methyl-2H-indazol-5-yl)-5-(2-methylpyridin-4-yl)furan-2-carboxamide;N-(6-(azepan-1-yl)-2-methyl-2H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide;N-(6-(azepan-1-yl)-1-methyl-1H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide;N-(2,3-dimethyl-6-(piperidin-1-yl)-2H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide;N-(1,3-dimethyl-6-(piperidin-1-yl)-1H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide;N-(6-(4-hydroxypiperidin-1-yl)-1-(2-methoxyethyl)-1H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide;76.N-(6-(4-hydroxypiperidin-1-yl)-2-(2-methoxyethyl)-2H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide;N-(6-(4-hydroxypiperidin-1-yl)-1-methyl-1H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide;N-(6-(4-fluoropiperidin-1-yl)-1-methyl-1H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide;N-(6-(3-fluoropiperidin-1-yl)-2-methyl-2H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide;N-(6-(4-(hydroxymethyl)piperidin-1-yl)-2-methyl-2H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide;N-(6-(4-hydroxypiperidin-1-yl)-1,3-dimethyl-1H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide;N-(6-(3-(hydroxymethyl)piperidin-1-yl)-2-methyl-2H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide;N-(6-(4-hydroxypiperidin-1-yl)-2,3-dimethyl-2H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide;2-(2-acetamidopyridin-4-yl)-N-(2-methyl-6-(piperidin-1-yl)-2H-indazol-5-yl)oxazole-4-carboxamide;2-(2-acetamidopyridin-4-yl)-N-(6-(3-fluoropiperidin-1-yl)-2-methyl-2H-indazol-5-yl)oxazole-4-carboxamide;2-(2-aminopyridin-4-yl)-N-(2-methyl-6-(piperidin-1-yl)-2H-indazol-5-yl)oxazole-4-carboxamidehydrochloride;N-(6-(4-fluoropiperidin-1-yl)-1,3-dimethyl-1H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide;N-(6-(((1R,4R)-4-hydroxycyclohexyl)amino)-2-methyl-2H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide;N-(6-(4-(hydroxymethyl)piperidin-1-yl)-1-methyl-1H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazole-1-carboxamide;2-(2-aminopyridin-4-yl)-N-(6-(4-fluoropiperidin-1-yl)-2-methyl-2H-indazol-5-yl)oxazole-4-carboxamidehydrochloride; 91.N-(6-(4-fluoropiperidin-1-yl)-2-methyl-2H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamidehydrochloride;(S)—N-(6-(4-(hydroxymethyl)piperidin-1-yl)-2-methyl-2H-indazol-5-yl)-6-(1-(2-hydroxypropyl)-1H-pyrazol-4-yl)picolinamide;2-(2-aminopyridin-4-yl)-N-(6-(4-hydroxypiperidin-1-yl)-2-methyl-2H-indazol-5-yl)oxazole-4-carboxamidehydrochloride; 94.N-(6-(4-(hydroxymethyl)piperidin-1-yl)-1-(2-methoxyethyl)-1H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide;(S)—N-(6-(4-(hydroxymethyl)piperidin-1-yl)-1-methyl-1H-indazol-5-yl)-6-(1-(2-hydroxypropyl)-1H-pyrazol-4-yl)picolinamide;N-(6-(4-(hydroxymethyl)piperidin-1-yl)-2-(2-methoxyethyl)-2H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide;97.N-(6-(4-(hydroxymethyl)piperidin-1-yl)-2-methyl-2H-indazol-5-yl)-2-(2-methoxypyridin-4-yl)oxazole-4-carboxamide;2-(2-acetamidopyridin-4-yl)-N-(6-(4-(hydroxymethyl)piperidin-1-yl)-2-methyl-2H-indazol-5-yl)oxazole-4-carboxamide;2-(2-aminopyridin-4-yl)-N-(6-(4-(hydroxymethyl)piperidin-1-yl)-1-methyl-1H-indazol-5-yl)oxazole-4-carboxamidehydrochloride;2-(2-aminopyridin-4-yl)-N-(6-(4-(hydroxymethyl)piperidin-1-yl)-2-methyl-2H-indazol-5-yl)oxazole-4-carboxamidehydrochloride;N-(6-(4-hydroxypiperidin-1-yl)-1-methyl-1H-indazol-5-yl)-2-(2-methoxypyridin-4-yl)oxazole-4-carboxamide;2-(2-aminopyridin-4-yl)-N-(6-(3-hydroxypiperidin-1-yl)-2-methyl-2H-indazol-5-yl)oxazole-4-carboxamidehydrochloride;2-(2-methoxypyridin-4-yl)-N-(2-methyl-6-(piperidin-1-yl)-2H-indazol-5-yl)oxazole-4-carboxamide;2-(2-aminopyridin-4-yl)-N-(6-(3-fluoropiperidin-1-yl)-2-methyl-2H-indazol-5-yl)oxazole-4-carboxamidehydrochloride;(R)-2-(2-aminopyridin-4-yl)-N-(6-(3-hydroxypyrrolidin-1-yl)-2-methyl-2H-indazol-5-yl)oxazole-4-carboxamidehydrochloride; 106.1-(1,3-dimethyl-5-(2-(2-methylpyridin-4-yl)oxazole-4-carboxamido)-1H-indazol-6-yl)piperidin-4-yl2-methoxyacetate;N-(6-(4-hydroxypiperidin-1-yl)-2-methyl-2H-indazol-5-yl)-2-(2-methoxypyridin-4-yl)oxazole-4-carboxamidehydrochloride;N-(6-(4-aminopiperidin-1-yl)-1-(2-methoxyethyl)-1H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamidehydrochloride;N-(6-(4-aminopiperidin-1-yl)-2-methyl-2H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamidehydrochloride;N-(6-(4-(hydroxymethyl)piperidin-1-yl)-1-(2-methoxyethyl)-3-methyl-1H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide;N-(6-(4-(hydroxymethyl)piperidin-1-yl)-1,3-dimethyl-1H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide;2-(2-aminopyridin-4-yl)-N-(6-(4-(hydroxymethyl)piperidin-1-yl)-1,3-dimethyl-1H-indazol-5-yl)oxazole-4-carboxamide;N-(6-(4-hydroxypiperidin-1-yl)-1-methyl-1H-indazol-5-yl)-2-(2-hydroxypyridin-4-yl)oxazole-4-carboxamide;2-(2,6-dimethylpyridin-4-yl)-N-(6-(4-hydroxypiperidin-1-yl)-1-methyl-1H-indazol-5-yl)oxazole-4-carboxamide;115.(S)—N-(6-(3-hydroxypyrrolidin-1-yl)-1-methyl-1H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide;N-(6-(4-hydroxypiperidin-1-yl)-1-(2-methoxyethyl)-3-methyl-1H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide;N-(1-(2-hydroxyethyl)-6-(4-hydroxypiperidin-1-yl)-1H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide;N-(6-(4-aminopiperidin-1-yl)-2-(2-methoxyethyl)-2H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamidehydrochloride;2-(2,6-dimethylpyridin-4-yl)-N-(2-methyl-6-(piperidin-1-yl)-2H-indazol-5-yl)oxazole-4-carboxamidehydrochloride;2-(2-(dimethylamino)pyridin-4-yl)-N-(2-methyl-6-(piperidin-1-yl)-2H-indazol-5-yl)oxazole-4-carboxamide;N-(6-(4-hydroxypiperidin-1-yl)-1-methyl-1H-indazol-5-yl)-2-(2-(methylamino)pyridin-4-yl)oxazole-4-carboxamide;122.N-(2-methyl-6-(piperidin-1-yl)-2H-indazol-5-yl)-2-(2-(methylamino)pyridin-4-yl)oxazole-4-carboxamide;N-(6-(4-hydroxypiperidin-1-yl)-2-methyl-2H-indazol-5-yl)-2-(2-(methylsulfonamido)pyridin-4-yl) oxazole-4-carboxamide; 2-(2-(dimethylamino)pyridin-4-yl)-N-(6-(4-hydroxypiperidin-1-yl)-1-methyl-1H-indazol-5-yl)oxazole-4-carboxamide;N-(6-(4-(aminomethyl)piperidin-1-yl)-1-(2-methoxyethyl)-1H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide;2-(2,6-dimethylpyridin-4-yl)-N-(6-(4-hydroxypiperidin-1-yl)-2-methyl-2H-indazol-5-yl)oxazole-4-carboxamide;2-(2,6-dimethylpyridin-4-yl)-N-(6-(4-fluoropiperidin-1-yl)-2-methyl-2H-indazol-5-yl)oxazole-4-carboxamide;Diethyl(1-(1-methyl-5-(2-(2-methylpyridin-4-yl)oxazole-4-carboxamido)-1H-indazol-6-yl)piperidin-4-yl)phosphate;andDiethyl((1-(2-methyl-5-(2-(2-methylpyridin-4-yl)oxazole-4-carboxamido)-2H-indazol-6-yl)piperidin-4-yl)methyl) phosphate.

In any aspect or embodiment described herein, R₆ of PTM-XIIIa-h is aC2-C6-alkyl radical substituted by 1, 2 or 3 fluorine atoms, such as:2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, and 4,4,4-trifluorobutyl.In any aspect or embodiment described herein, R₆ is a C2-C5-alkylradical substituted by one or two hydroxyl group(s) or one C1-C3-alkoxyor a tri-fluorine-substituted C1-C3-alkoxy, such as: C2-C5-alkyl radicalsubstituted by hydroxyl or C1-C3-alkoxy or trifluoromethoxy or2,2,2-trifluoroethoxy or trifluoromethyl, 3-hydroxy-3-methylbutyl,3-methoxypropyl, 3-hydroxypropyl, 3-trifluoromethoxypropyl,2-methoxyethyl or 2-hydroxyethyl. In any aspect or embodiment describedherein, R₆ of PTM-XIIIa-h is a C2-C5-alkyl radical substituted by aC1-C6-alkyi-SO₂ group, such as: methyi-SO₂-substituted C2-C4-alkylradical, 2-(methylsulphonyl)ethyl or 3-(methylsulphonyl)propyl.

In any aspect or embodiment described herein, R₆ of PTM-XIIIa-h is aC1-C3-alkyl radical substituted by oxetanyl, tetrahydrofuranyl,tetrahydro-2H-pyran-4-yl, 1,1-dioxidotetrahydro-2H-thiopyran-3-yl,1,1-dioxidotetrahydro-2H-thiopyran-2-yl,1,1-dioxidotetrahydro-2H-thiopyran-4-yl,1,1-dioxidotetrahydrothiophen-3-yl, 1,1-dioxidotetrahydrothiophen-2-yl,1,1-dioxidothietan-2-yl or 1,1-dioxidothietan-3-yl. Particularpreference is given to a C1-C3-alkyl radical substituted by an oxetanegroup. For example, R⁶ may be a oxetan-3-ylmethyl group

In any aspect or embodiment described herein, R₇ and R⁸ areindependently selected from hydrogen methyl.

In any aspect or embodiment described herein, R₄ of PTM-XIIIa-h is anunsubstituted or mono- or poly-halogensubstituted C1-C3-alkyl radical ora C1-C3-alkyl radical, e.g., optionally substituted by one hydroxylgroup or a C1-C3-alkyl radical substituted by one hydroxyl group andthree fluorine atoms), such as: methyl, trifluoromethyl, difluoromethyl,ethyl, trifluoro-C1-C3-alkyl, difluoro-C1-C3-alkyl, hydroxymethyl,1-hydroxyethyl, 2-hydroxypropan-2-yl and 2,2,2-trifluoro-1-hydroxyethyl.

In any aspect or embodiment described herein, R⁵ of PTM-XIIIa-h ishydrogen, fluorine, methyl, chlorine or C1-C3-alkyl.

In any aspect or embodiment described herein, R₄ of PTM-XIIIa-h ismethyl or trifluoromethyl, and R⁵ is fluorine (e.g. fluorine in theortho position to R⁴).

In any aspect or embodiment described herein, R₉ of PTM-XIIIa-h isoxetanyl, oxetan-3-yl, tetrahydrofuranyl, tetrahydro-2H-pyran-4-yl,1,1-dioxidotetrahydro-2H-thiopyran-3-yl,1,1-dioxidotetrahydro-2H-thiopyran-2-yl,1,1-dioxidotetrahydro-2H-thiopyran-4-yl,1,1-dioxidotetrahydrothiophen-3-yl, 1,1-dioxidotetrahydrothiophen-2-yl,1,1-dioxidothietan-2-yl or 1,1-dioxidothietan-3-yl.

In any aspect or embodiment described herein, R₁₀ of PTM-XIIIa-h isexclusively connected to the functional groups —SO₂— and —SO—, i.e. isan R₁₀-substituted —SO₂— or SO group. In this connection, R₁₀ ofPTM-XIIIa-h is preferably C1-C4-alkyl, where the C1-C4-alkyl radical isunsubstituted or monosubstituted by hydroxyl or by cyclopropyl orsubstituted by three fluorine atoms. In any aspect or embodimentdescribed herein, R₁₀ is cyclopropyl radical, methyl, ethyl orhydroxyethyl.

In any aspect or embodiment described herein, R of PTM-XIIIa-h is anunsubstituted C1-C4-alkyl radical or a tri-fluorine-substitutedC1-C4-alkyl radical, such as: methyl, ethyl, trifluoromethyl or2,2,2-trifluoroethyl.

In any aspect or embodiment described herein, the PTM-XIIIa-h isselected from the group consisting of:N-[6-(2-hydroxypropan-2-yl)-2-(2-methoxyethyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide;N-[6-(hydroxymethyl)-2-(2-methoxyethyi)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide;N-[6-(2-hydroxypropan-2-yl)-2-(3-methoxypropyi)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide;N-[6-(hydroxymethyl)-2-(3-methoxypropyi)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide;N-[2-(2-hydroxyethyl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide;N-[6-(2-hydroxypropan-2-yl)-2-(3-hydroxypropyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide;N-[2-(2-hydroxyethyl)-6-(hydroxymethyi)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide;N-[6-(2-hydroxypropan-2-yl)-2-(oxetan-3-ylmethyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide;N-[6-(hydroxymethyl)-2-(oxetan-3-ylmethyi)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide;N-{6-(2-hydroxypropan-2-yl)-2-[3-(methylsulphonyl)propyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide;N-[2-(3-hydroxy-3-methylbutyl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide;N-{6-(2-hydroxypropan-2-yl)-2-[2-(methylsulphonyl)ethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide;6-(difluoromethyi)-N-[2-(3-hydroxy-3-methylbutyl)-6-(2-hydroxypropan-2-yi)-2Hindazol-5-yl]pyridine-2-carboxamide;6-(difluoromethyi)-N-{6-(2-hydroxypropan-2-yl)-2-[2-(methylsulphonyl)ethyi]-2Hindazol-5-yl}pyridine-2-carboxamide;6-(difluoromethyl)-N-[6-(2-hydroxypropan-2-yl)-2-(3-hydroxypropyl)-2H-indazol-5-yl]pyridine-2-carboxamide;N-[6-(2-hydroxypropan-2-yl)-2-(4,4,4-trifluorobutyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide;N-{6-(2-hydroxypropan-2-yl)-2-[3-(trifluoromethoxy)propyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide;N-{6-(2-hydroxypropan-2-yl)-2-[3-(2,2,2-trifluoroethoxy)propyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide;5-fluoro-N-[2-(3-hydroxy-3-methylbutyl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl]-6-methylpyridine-2-carboxamide;N-[2-(3-hydroxy-3-methylbutyl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl]-6-methylpyridine-2-carboxamide;6-(2-hydroxypropan-2-yi)-N-[6-(2-hydroxypropan-2-yl)-2-(4,4,4-trifluorobutyi)-2Hindazol-5-yl]pyridine-2-carboxamide.

In any aspect or embodiment described herein, the PTM is selected fromthe group consisting of:

In any aspect or embodiment described herein, the PTM is selected from

Therapeutic Compositions

Pharmaceutical compositions comprising combinations of an effectiveamount of at least one bifunctional compound as described herein, andone or more of the compounds otherwise described herein, all ineffective amounts, in combination with a pharmaceutically effectiveamount of a carrier, additive or excipient, represents a further aspectof the present disclosure.

The present disclosure includes, where applicable, the compositionscomprising the pharmaceutically acceptable salts, in particular, acid orbase addition salts of compounds as described herein. The acids whichare used to prepare the pharmaceutically acceptable acid addition saltsof the aforementioned base compounds useful according to this aspect arethose which form non-toxic acid addition salts, i.e., salts containingpharmacologically acceptable anions, such as the hydrochloride,hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acidphosphate, acetate, lactate, citrate, acid citrate, tartrate,bitartrate, succinate, maleate, fumarate, gluconate, saccharate,benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate,p-toluenesulfonate and pamoate [i.e., 1,1′-methylene-bis-(2-hydroxy-3naphthoate)]salts, among numerous others.

Pharmaceutically acceptable base addition salts may also be used toproduce pharmaceutically acceptable salt forms of the compounds orderivatives according to the present disclosure. The chemical bases thatmay be used as reagents to prepare pharmaceutically acceptable basesalts of the present compounds that are acidic in nature are those thatform non-toxic base salts with such compounds. Such non-toxic base saltsinclude, but are not limited to those derived from suchpharmacologically acceptable cations such as alkali metal cations (eg.,potassium and sodium) and alkaline earth metal cations (eg, calcium,zinc and magnesium), ammonium or water-soluble amine addition salts suchas N-methylglucamine-(meglumine), and the lower alkanolammonium andother base salts of pharmaceutically acceptable organic amines, amongothers.

The compounds as described herein may, in accordance with thedisclosure, be administered in single or divided doses by the oral,parenteral or topical routes. Administration of the active compound mayrange from continuous (intravenous drip) to several oral administrationsper day (for example, Q.I.D.) and may include oral, topical, parenteral,intramuscular, intravenous, sub-cutaneous, transdermal (which mayinclude a penetration enhancement agent), buccal, sublingual andsuppository administration, among other routes of administration.Enteric coated oral tablets may also be used to enhance bioavailabilityof the compounds from an oral route of administration. The mosteffective dosage form will depend upon the pharmacokinetics of theparticular agent chosen as well as the severity of disease in thepatient. Administration of compounds according to the present disclosureas sprays, mists, or aerosols for intra-nasal, intra-tracheal orpulmonary administration may also be used. The present disclosuretherefore also is directed to pharmaceutical compositions comprising aneffective amount of compound as described herein, optionally incombination with a pharmaceutically acceptable carrier, additive orexcipient. Compounds according to the present disclosure ion may beadministered in immediate release, intermediate release or sustained orcontrolled release forms. Sustained or controlled release forms arepreferably administered orally, but also in suppository and transdermalor other topical forms. Intramuscular injections in liposomal form mayalso be used to control or sustain the release of compound at aninjection site.

The compositions as described herein may be formulated in a conventionalmanner using one or more pharmaceutically acceptable carriers and mayalso be administered in controlled-release formulations.Pharmaceutically acceptable carriers that may be used in thesepharmaceutical compositions include, but are not limited to, ionexchangers, alumina, aluminum stearate, lecithin, serum proteins, suchas human serum albumin, buffer substances such as phosphates, glycine,sorbic acid, potassium sorbate, partial glyceride mixtures of saturatedvegetable fatty acids, water, salts or electrolytes, such as prolaminesulfate, disodium hydrogen phosphate, potassium hydrogen phosphate,sodium chloride, zinc salts, colloidal silica, magnesium trisilicate,polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol,sodium carboxymethylcellulose, polyacrylates, waxes,polyethylene-polyoxypropylene-block polymers, polyethylene glycol andwool fat.

The compositions as described herein may be administered orally,parenterally, by inhalation spray, topically, rectally, nasally,buccally, vaginally or via an implanted reservoir. The term “parenteral”as used herein includes subcutaneous, intravenous, intramuscular,intra-articular, intra-synovial, intrasternal, intrathecal,intrahepatic, intralesional and intracranial injection or infusiontechniques. Preferably, the compositions are administered orally,intraperitoneally or intravenously.

Sterile injectable forms of the compositions as described herein may beaqueous or oleaginous suspension. These suspensions may be formulatedaccording to techniques known in the art using suitable dispersing orwetting agents and suspending agents. The sterile injectable preparationmay also be a sterile injectable solution or suspension in a non-toxicparenterally-acceptable diluent or solvent, for example as a solution in1, 3-butanediol. Among the acceptable vehicles and solvents that may beemployed are water, Ringer's solution and isotonic sodium chloridesolution. In addition, sterile, fixed oils are conventionally employedas a solvent or suspending medium. For this purpose, any bland fixed oilmay be employed including synthetic mono- or di-glycerides. Fatty acids,such as oleic acid and its glyceride derivatives are useful in thepreparation of injectables, as are natural pharmaceutically-acceptableoils, such as olive oil or castor oil, especially in theirpolyoxyethylated versions. These oil solutions or suspensions may alsocontain a long-chain alcohol diluent or dispersant, such as Ph. Helv orsimilar alcohol.

The pharmaceutical compositions as described herein may be orallyadministered in any orally acceptable dosage form including, but notlimited to, capsules, tablets, aqueous suspensions or solutions. In thecase of tablets for oral use, carriers which are commonly used includelactose and corn starch. Lubricating agents, such as magnesium stearate,are also typically added. For oral administration in a capsule form,useful diluents include lactose and dried corn starch. When aqueoussuspensions are required for oral use, the active ingredient is combinedwith emulsifying and suspending agents. If desired, certain sweetening,flavoring or coloring agents may also be added.

Alternatively, the pharmaceutical compositions as described herein maybe administered in the form of suppositories for rectal administration.These can be prepared by mixing the agent with a suitable non-irritatingexcipient, which is solid at room temperature but liquid at rectaltemperature and therefore will melt in the rectum to release the drug.Such materials include cocoa butter, beeswax and polyethylene glycols.

The pharmaceutical compositions as described herein may also beadministered topically. Suitable topical formulations are readilyprepared for each of these areas or organs. Topical application for thelower intestinal tract can be effected in a rectal suppositoryformulation (see above) or in a suitable enema formulation.Topically-acceptable transdermal patches may also be used.

For topical applications, the pharmaceutical compositions may beformulated in a suitable ointment containing the active componentsuspended or dissolved in one or more carriers. Carriers for topicaladministration of the compounds of this disclosure include, but are notlimited to, mineral oil, liquid petrolatum, white petrolatum, propyleneglycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax andwater. In certain preferred aspects of the disclosure, the compounds maybe coated onto a stent which is to be surgically implanted into apatient in order to inhibit or reduce the likelihood of occlusionoccurring in the stent in the patient.

Alternatively, the pharmaceutical compositions can be formulated in asuitable lotion or cream containing the active components suspended ordissolved in one or more pharmaceutically acceptable carriers. Suitablecarriers include, but are not limited to, mineral oil, sorbitanmonostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol,2-octyldodecanol, benzyl alcohol and water.

For ophthalmic use, the pharmaceutical compositions may be formulated asmicronized suspensions in isotonic, pH adjusted sterile saline, or,preferably, as solutions in isotonic, pH adjusted sterile saline, eitherwith our without a preservative such as benzylalkonium chloride.Alternatively, for ophthalmic uses, the pharmaceutical compositions maybe formulated in an ointment such as petrolatum.

The pharmaceutical compositions as described herein may also beadministered by nasal aerosol or inhalation. Such compositions areprepared according to techniques well-known in the art of pharmaceuticalformulation and may be prepared as solutions in saline, employing benzylalcohol or other suitable preservatives, absorption promoters to enhancebioavailability, fluorocarbons, and/or other conventional solubilizingor dispersing agents.

The amount of compound in a pharmaceutical composition as describedherein that may be combined with the carrier materials to produce asingle dosage form will vary depending upon the host and diseasetreated, the particular mode of administration. Preferably, thecompositions should be formulated to contain between about 0.05milligram to about 750 milligrams or more, more preferably about 1milligram to about 600 milligrams, and even more preferably about 10milligrams to about 500 milligrams of active ingredient, alone or incombination with at least one other compound according to the presentdisclosure.

It should also be understood that a specific dosage and treatmentregimen for any particular patient will depend upon a variety offactors, including the activity of the specific compound employed, theage, body weight, general health, sex, diet, time of administration,rate of excretion, drug combination, and the judgment of the treatingphysician and the severity of the particular disease or condition beingtreated.

A patient or subject in need of therapy using compounds according to themethods described herein can be treated by administering to the patient(subject) an effective amount of the compound according to the presentdisclosure including pharmaceutically acceptable salts, solvates orpolymorphs, thereof optionally in a pharmaceutically acceptable carrieror diluent, either alone, or in combination with other knownerythopoiesis stimulating agents as otherwise identified herein.

These compounds can be administered by any appropriate route, forexample, orally, parenterally, intravenously, intradermally,subcutaneously, or topically, including transdermally, in liquid, cream,gel, or solid form, or by aerosol form.

The active compound is included in the pharmaceutically acceptablecarrier or diluent in an amount sufficient to deliver to a patient atherapeutically effective amount for the desired indication, withoutcausing serious toxic effects in the patient treated. A preferred doseof the active compound for all of the herein-mentioned conditions is inthe range from about 10 ng/kg to 300 mg/kg, preferably 0.1 to 100 mg/kgper day, more generally 0.5 to about 25 mg per kilogram body weight ofthe recipient/patient per day. A typical topical dosage will range from0.01-5% wt/wt in a suitable carrier.

The compound is conveniently administered in any suitable unit dosageform, including but not limited to one containing less than 1 mg, 1 mgto 3000 mg, preferably 5 to 500 mg of active ingredient per unit dosageform. An oral dosage of about 25-250 mg is often convenient.

The active ingredient is preferably administered to achieve peak plasmaconcentrations of the active compound of about 0.00001-30 mM, preferablyabout 0.1-30 μM. This may be achieved, for example, by the intravenousinjection of a solution or formulation of the active ingredient,optionally in saline, or an aqueous medium or administered as a bolus ofthe active ingredient. Oral administration is also appropriate togenerate effective plasma concentrations of active agent.

The concentration of active compound in the drug composition will dependon absorption, distribution, inactivation, and excretion rates of thedrug as well as other factors known to those of skill in the art. It isto be noted that dosage values will also vary with the severity of thecondition to be alleviated. It is to be further understood that for anyparticular subject, specific dosage regimens should be adjusted overtime according to the individual need and the professional judgment ofthe person administering or supervising the administration of thecompositions, and that the concentration ranges set forth herein areexemplary only and are not intended to limit the scope or practice ofthe claimed composition. The active ingredient may be administered atonce, or may be divided into a number of smaller doses to beadministered at varying intervals of time.

Oral compositions will generally include an inert diluent or an ediblecarrier. They may be enclosed in gelatin capsules or compressed intotablets. For the purpose of oral therapeutic administration, the activecompound or its prodrug derivative can be incorporated with excipientsand used in the form of tablets, troches, or capsules. Pharmaceuticallycompatible binding agents, and/or adjuvant materials can be included aspart of the composition.

The tablets, pills, capsules, troches and the like can contain any ofthe following ingredients, or compounds of a similar nature: a bindersuch as microcrystalline cellulose, gum tragacanth or gelatin; anexcipient such as starch or lactose, a dispersing agent such as alginicacid, Primogel, or corn starch; a lubricant such as magnesium stearateor Sterotes; a glidant such as colloidal silicon dioxide; a sweeteningagent such as sucrose or saccharin; or a flavoring agent such aspeppermint, methyl salicylate, or orange flavoring. When the dosage unitform is a capsule, it can contain, in addition to material of the abovetype, a liquid carrier such as a fatty oil. In addition, dosage unitforms can contain various other materials which modify the physical formof the dosage unit, for example, coatings of sugar, shellac, or entericagents.

The active compound or pharmaceutically acceptable salt thereof can beadministered as a component of an elixir, suspension, syrup, wafer,chewing gum or the like. A syrup may contain, in addition to the activecompounds, sucrose as a sweetening agent and certain preservatives, dyesand colorings and flavors.

The active compound or pharmaceutically acceptable salts thereof canalso be mixed with other active materials that do not impair the desiredaction, or with materials that supplement the desired action, such aserythropoietin stimulating agents, including EPO and darbapoietin alfa,among others. In certain preferred aspects of the disclosure, one ormore compounds according to the present disclosure are coadministeredwith another bioactive agent, such as an erythropoietin stimulatingagent or a would healing agent, including an antibiotic, as otherwisedescribed herein.

Solutions or suspensions used for parenteral, intradermal, subcutaneous,or topical application can include the following components: a sterilediluent such as water for injection, saline solution, fixed oils,polyethylene glycols, glycerine, propylene glycol or other syntheticsolvents; antibacterial agents such as benzyl alcohol or methylparabens; antioxidants such as ascorbic acid or sodium bisulfite;chelating agents such as ethylenediaminetetraacetic acid; buffers suchas acetates, citrates or phosphates and agents for the adjustment oftonicity such as sodium chloride or dextrose. The parental preparationcan be enclosed in ampoules, disposable syringes or multiple dose vialsmade of glass or plastic.

If administered intravenously, preferred carriers are physiologicalsaline or phosphate buffered saline (PBS).

In one embodiment, the active compounds are prepared with carriers thatwill protect the compound against rapid elimination from the body, suchas a controlled release formulation, including implants andmicroencapsulated delivery systems. Biodegradable, biocompatiblepolymers can be used, such as ethylene vinyl acetate, polyanhydrides,polyglycolic acid, collagen, polyorthoesters, and polylactic acid.Methods for preparation of such formulations will be apparent to thoseskilled in the art.

Liposomal suspensions may also be pharmaceutically acceptable carriers.These may be prepared according to methods known to those skilled in theart, for example, as described in U.S. Pat. No. 4,522,811 (which isincorporated herein by reference in its entirety). For example, liposomeformulations may be prepared by dissolving appropriate lipid(s) (such asstearoyl phosphatidyl ethanolamine, stearoyl phosphatidyl choline,arachadoyl phosphatidyl choline, and cholesterol) in an inorganicsolvent that is then evaporated, leaving behind a thin film of driedlipid on the surface of the container. An aqueous solution of the activecompound are then introduced into the container. The container is thenswirled by hand to free lipid material from the sides of the containerand to disperse lipid aggregates, thereby forming the liposomalsuspension.

Therapeutic Methods

In an additional aspect, the description provides therapeuticcompositions comprising an effective amount of a compound as describedherein or salt form thereof, and a pharmaceutically acceptable carrier.The therapeutic compositions modulate protein degradation in a patientor subject, for example, an animal such as a human, and can be used fortreating or ameliorating disease states or conditions which aremodulated through the degraded protein.

The terms “treat”, “treating”, and “treatment”, etc., as used herein,refer to any action providing a benefit to a patient for which thepresent compounds may be administered, including the treatment of anydisease state or condition which is modulated through the protein towhich the present compounds bind. Disease states or conditions,including cancer, inflammatory diseases/disorders, autoimmunediseases/disorders, neurodegenerative diseases, and/or cardiovasculardiseases/disorders, which may be treated using compounds according tothe present disclosure are set forth hereinabove.

The description provides therapeutic compositions as described hereinfor effectuating the degradation of proteins of interest for thetreatment or amelioration of a disease, e.g., cancer, inflammatorydiseases/disorders, autoimmune diseases/disorders, neurodegenerativediseases, and/or cardiovascular diseases/disorders. In certainadditional embodiments, the disease is cancer or an inflammationdisorder. As such, in another aspect, the description provides a methodof ubiquitinating/degrading a target protein in a cell. In certainembodiments, the method comprises administering a bifunctional compoundas described herein comprising, e.g., a ULM and a PTM, preferably linkedthrough a linker moiety, as otherwise described herein, wherein the UMis coupled to the PTM and wherein the ULM recognizes a ubiquitin pathwayprotein (e.g., an ubiquitin ligase, such as an E3 ubiquitin ligaseincluding cereblon, VHL, IAP, and/or MDM2) and the PTM recognizes thetarget protein such that degradation of the target protein will occurwhen the target protein is placed in proximity to the ubiquitin ligase,thus resulting in degradation/inhibition of the effects of the targetprotein and the control of protein levels. The control of protein levelsafforded by the present disclosure provides treatment of a disease stateor condition, which is modulated through the target protein by loweringthe level of that protein in the cell, e.g., cell of a patient. Incertain embodiments, the method comprises administering an effectiveamount of a compound as described herein, optionally including apharmaceutically acceptable excipient, carrier, adjuvant, anotherbioactive agent or combination thereof.

In additional embodiments, the description provides methods for treatingor emeliorating a disease, disorder or symptom thereof in a subject or apatient, e.g., an animal such as a human, comprising administering to asubject in need thereof a composition comprising an effective amount,e.g., a therapeutically effective amount, of a compound as describedherein or salt form thereof, and a pharmaceutically acceptableexcipient, carrier, adjuvant, another bioactive agent or combinationthereof, wherein the composition is effective for treating orameliorating the disease or disorder or symptom thereof in the subject.

In another aspect, the description provides methods for identifying theeffects of the degradation of proteins of interest in a biologicalsystem using compounds according to the present disclosure.

In another embodiment, the present disclosure is directed to a method oftreating a human patient in need for a disease state or conditionmodulated through a protein where the degradation of that protein willproduce a therapeutic effect in that patient, the method comprisingadministering to a patient in need an effective amount of a compoundaccording to the present disclosure, optionally in combination withanother bioactive agent. The disease state or condition may be a diseasecaused by a microbial agent or other exogenous agent such as a virus,bacteria, fungus, protozoa or other microbe or may be a disease state,which is caused by overexpression of a protein, which leads to a diseasestate and/or condition

The term “disease state or condition” is used to describe any diseasestate or condition wherein protein dysregulation (i.e., the amount ofprotein expressed in a patient is elevated) occurs and where degradationof one or more proteins in a patient may provide beneficial therapy orrelief of symptoms to a patient in need thereof. In certain instances,the disease state or condition may be cured.

Disease states of conditions which may be treated using compoundsaccording to the present disclosure include, for example, asthma,autoimmune diseases such as multiple sclerosis, various cancers,ciliopathies, cleft palate, diabetes, heart disease, hypertension,inflammatory bowel disease, mental retardation, mood disorder, obesity,refractive error, infertility, Angelman syndrome, Canavan disease,Coeliac disease, Charcot-Marie-Tooth disease, Cystic fibrosis, Duchennemuscular dystrophy, Haemochromatosis, Haemophilia, Klinefelter'ssyndrome, Neurofibromatosis, Phenylketonuria, Polycystic kidney disease,(PKD1) or 4 (PKD2) Prader-Willi syndrome, Sickle-cell disease, Tay-Sachsdisease, Turner syndrome.

In any aspect or embodiment described herein, the disease states ofconditions that may be treated using the composition and/or compound ofthe present disclosure is at least one of: a cancer, an inflammatorydisorder, an autoimmune disease, metabolic disorder, a hereditarydisorder, a hormone-related disease, immunodeficiency disorders, acondition associated with cell death, a destructive bone disorder,thrombin-induced platelet aggregation, liver disease and acardiovascular disorder.

In any aspect or embodiment described herein, the disease states ofconditions that may be treated using compounds according to the presentdisclosure include, for example, at least one of: (A) pulmonary diseasesand diseases of the airway including, but not limited to, AdultRespiratory Disease Syndrome (ARDS), Chronic Obstructive PulmonaryDisease (COPD), pulmonary fibrosis, interstitial lung disease, asthma,chronic cough, and allergic rhinitis, (B) transplantation, (C) theautoimmune diseases including, but not limited to, rheumatoid arthritis,systemic lupus erythematosus, multiple sclerosis, and diabetes (e g,type 1 diabetes mellitus), (D) cancer including, but not limited to,solid tumors, skin cancer and lymphoma, (E) cardiovascular diseasesincluding, but not limited to, stroke and atherosclerosis, (F) diseasesof the central nervous system including, but not limited to,neurodegenerative diseases, (G) non-CD 14 mediated sepsis, (H)osteoarthritis, (I) osteoporosis, (J) psoriasis and diseases of the skinincluding, but not limited to, rash and contact and atopic dermatitis,(K) inflammatory disorders; (L) inflammatory bowel disease (including,but not limited to, Crohn's disease and ulcerative colitis), (M)Behcet's syndrome, (N) ankylosing spondylitis, (O) sarcoidosis, (P)gout, (Q) ophthalmic diseases and conditions, and (R) CD14 mediatedsepsis. In such patients, the inhibition and/or degradation of IRAK-4in, e g, IL-1 responsive cells will block the transduction of the IL-1initiated signal, thereby preventing NF-KB activation and thus providinga treatment for the disorder or disorders.

The term “neoplasia” or “cancer” is used throughout the specification torefer to the pathological process that results in the formation andgrowth of a cancerous or malignant neoplasm, i.e., abnormal tissue thatgrows by cellular proliferation, often more rapidly than normal andcontinues to grow after the stimuli that initiated the new growth cease.Malignant neoplasms show partial or complete lack of structuralorganization and functional coordination with the normal tissue and mostinvade surrounding tissues, metastasize to several sites, and are likelyto recur after attempted removal and to cause the death of the patientunless adequately treated. As used herein, the term neoplasia is used todescribe all cancerous disease states and embraces or encompasses thepathological process associated with malignant hematogenous, ascitic andsolid tumors. Exemplary cancers which may be treated by the presentcompounds either alone or in combination with at least one additionalanti-cancer agent include squamous-cell carcinoma, basal cell carcinoma,adenocarcinoma, hepatocellular carcinomas, and renal cell carcinomas,cancer of the bladder, bowel, breast, cervix, colon, esophagus, head,kidney, liver, lung, neck, ovary, pancreas, prostate, and stomach;leukemias; benign and malignant lymphomas, particularly Burkitt'slymphoma and Non-Hodgkin's lymphoma; benign and malignant melanomas;myeloproliferative diseases; sarcomas, including Ewing's sarcoma,hemangiosarcoma, Kaposi's sarcoma, liposarcoma, myosarcomas, peripheralneuroepithelioma, synovial sarcoma, gliomas, astrocytomas,oligodendrogliomas, ependymomas, gliobastomas, neuroblastomas,ganglioneuromas, gangliogliomas, medulloblastomas, pineal cell tumors,meningiomas, meningeal sarcomas, neurofibromas, and Schwannomas; bowelcancer, breast cancer, prostate cancer, cervical cancer, uterine cancer,lung cancer, ovarian cancer, testicular cancer, thyroid cancer,astrocytoma, esophageal cancer, pancreatic cancer, stomach cancer, livercancer, colon cancer, melanoma; carcinosarcoma, Hodgkin's disease,Wilms' tumor and teratocarcinomas. Additional cancers which may betreated using compounds according to the present disclosure include, forexample, T-lineage Acute lymphoblastic Leukemia (T-ALL), T-lineagelymphoblastic Lymphoma (T-LL), Peripheral T-cell lymphoma, Adult T-cellLeukemia, Pre-B ALL, Pre-B Lymphomas, Large B-cell Lymphoma, BurkittsLymphoma, B-cell ALL, Philadelphia chromosome positive ALL andPhiladelphia chromosome positive CML.

In any aspect or embodiment described herein, the cancer may be selectedfrom the group consisting of breast cancer, colorectal cancer, non-smallcell lung cancer, ovarian, renal, sarcoma, melanoma, head & neck,hepatocellular, thyroid, multidrug-resistant leukemia, lymphoma,multiple myeloma, esophageal, large bowel, pancreatic, mesothelioma,carcinoma (e.g. adenocarcinoma, including esophageal adenocarcinoma),sarcoma (e.g. spindle cell sarcoma, liposarcoma, leiomyosarcoma,abdominal leiomyosarcoma, sclerosing epithelioid sarcoma) and melanoma(e.g. metastatic malignant melanoma).

In any aspect or embodiment described herein, the inflammatorydisease/disorder is selected from the group consisting of ocularallergy, conjunctivitis, keratoconjunctivitis sicca, vernalconjunctivitis, allergic rhinitis, autoimmune hematological disorders(e.g. hemolytic anemia, aplastic anemia, pure red cell anemia andidiopathic thrombocytopenia), systemic lupus erythematosus, rheumatoidarthritis, polychondritis, scleroderma, Wegener granulamatosis,dermatomyositis, chronic active hepatitis, myasthenia gravis,Steven-Johnson syndrome, idiopathic sprue, autoimmune inflammatory boweldisease (e.g. ulcerative colitis and Crohn's disease), irritable bowelsyndrome, celiac disease, periodontitis, hyaline membrane disease,kidney disease, glomerular disease, alcoholic liver disease, multiplesclerosis, endocrine opthalmopathy, Grave's disease, sarcoidosis,alveolitis, chronic hypersensitivity pneumonitis, primary biliarycirrhosis, uveitis (anterior and posterior), Sjogren's syndrome,interstitial lung fibrosis, psoriatic arthritis, systemic juvenileidiopathic arthritis, nephritis, vasculitis, diverticulitis,interstitial cystitis, glomerulonephritis (e.g. including idiopathicnephrotic syndrome or minimal change nephropathy), chronic granulomatousdisease, endometriosis, leptospirosis renal disease, glaucoma, retinaldisease, headache, pain, complex regional pain syndrome, cardiachypertrophy, muscle wasting, catabolic disorders, obesity, fetal growthretardation, hypercholesterolemia, heart disease, chronic heart failure,mesothelioma, anhidrotic ecodermal dysplasia, Behcet's disease,incontinentia pigmenti, Paget's disease, pancreatitis, hereditaryperiodic fever syndrome, asthma, acute lung injury, acute respiratorydistress syndrome, eosinophilia, hypersensitivities, anaphylaxis,fibrositis, gastritis, gastroenteritis, nasal sinusitis, ocular allergy,silica induced diseases, chronic obstructive pulmonary disease (COPD),cystic fibrosis, acid-induced lung injury, pulmonary hypertension,polyneuropathy, cataracts, muscle inflammation in conjunction withsystemic sclerosis, inclusion body myositis, myasthenia gravis,thyroiditis, Addison's disease, lichen planus, appendicitis, atopicdermatitis, asthma, allergy, blepharitis, bronchiolitis, bronchitis,bursitis, cervicitis, cholangitis, cholecystitis, chronic graftrejection, colitis, conjunctivitis, cystitis, dacryoadenitis,dermatitis, juvenile rheumatoid arthritis, dermatomyositis,encephalitis, endocarditis, endometritis, enteritis, enterocolitis,epicondylitis, epididymitis, fasciitis, Henoch-Schonlein purpura,hepatitis, hidradenitis suppurativa, immunoglobulin A nephropathy,interstitial lung disease, laryngitis, mastitis, meningitis, myelitismyocarditis, myositis, nephritis, oophoritis, orchitis, osteitis,otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis,pleuritis, phlebitis, pneumonitis, pneumonia, polymyositis, proctitis,prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis,stomatitis, synovitis, tendonitis, tonsillitis, ulcerative colitis,vasculitis, vulvitis, alopecia areata, erythema multiforma, dermatitisherpetiformis, scleroderma, vitiligo, hypersensitivity angiitis,urticaria, bullous pemphigoid, pemphigus vulgaris, pemphigus foliaceus,paraneoplastic pemphigus, epidermolysis bullosa acquisita, acute andchronic gout, chronic gouty arthritis, psoriasis, psoriatic arthritis,rheumatoid arthritis, Cryopyrin Associated Periodic Syndrome (CAPS) andosteoarthritis.

In any aspect or embodiment described herein, the neurodegenerativedisease may be selected from the group consisting of Alzheimer'sdisease, Parkinson's disease, amyotrophic lateral sclerosis,Huntington's disease, cerebral ischemia and neurodegenerative diseasecaused by traumatic injury, glutamate neurotoxicity, hypoxia, epilepsyand graft versus host disease.

The term “bioactive agent” is used to describe an agent, other than acompound according to the present disclosure, which is used incombination with the present compounds as an agent with biologicalactivity to assist in effecting an intended therapy, inhibition and/orprevention/prophylaxis for which the present compounds are used.Preferred bioactive agents for use herein include those agents whichhave pharmacological activity similar to that for which the presentcompounds are used or administered and include for example, anti-canceragents, anti-inflammatory agents, antiviral agents, especially includinganti-HIV agents and anti-HCV agents, antimicrobial agents, antifungalagents, etc.

The term “additional anti-cancer agent” is used to describe ananti-cancer agent, which may be combined with compounds according to thepresent disclosure to treat cancer. These agents include, for example,everolimus, trabectedin, abraxane, TLK 286, AV-299, DN-101, pazopanib,GSK690693, RTA 744, ON 0910.Na, AZD 6244 (ARRY-142886), AMN-107,TKI-258, GSK461364, AZD 1152, enzastaurin, vandetanib, ARQ-197, MK-0457,MLN8054, PHA-739358, R-763, AT-9263, a FLT-3 inhibitor, a VEGFRinhibitor, an EGFR TK inhibitor, an aurora kinase inhibitor, a PIK-1modulator, a Bcl-2 inhibitor, an HDAC inhbitor, a c-MET inhibitor, aPARP inhibitor, a Cdk inhibitor, an EGFR TK inhibitor, an IGFR-TKinhibitor, an anti-HGF antibody, a PI3 kinase inhibitor, an AKTinhibitor, an mTORC1/2 inhibitor, a JAK/STAT inhibitor, a checkpoint-1or 2 inhibitor, a focal adhesion kinase inhibitor, a Map kinase kinase(mek) inhibitor, a VEGF trap antibody, pemetrexed, erlotinib, dasatanib,nilotinib, decatanib, panitumumab, amrubicin, oregovomab, Lep-etu,nolatrexed, azd2171, batabulin, ofatumumab, zanolimumab, edotecarin,tetrandrine, rubitecan, tesmilifene, oblimersen, ticilimumab,ipilimumab, gossypol, Bio 111, 131-I-TM-601, ALT-110, BIO 140, CC 8490,cilengitide, gimatecan, IL13-PE38QQR, INO 1001, IPdR₁ KRX-0402,lucanthone, LY317615, neuradiab, vitespan, Rta 744, Sdx 102, talampanel,atrasentan, Xr 311, romidepsin, ADS-100380, sunitinib, 5-fluorouracil,vorinostat, etoposide, gemcitabine, doxorubicin, liposomal doxorubicin,5′-deoxy-5-fluorouridine, vincristine, temozolomide, ZK-304709,seliciclib; PD0325901, AZD-6244, capecitabine, L-Glutamic acid,N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-,disodium salt, heptahydrate, camptothecin, PEG-labeled irinotecan,tamoxifen, toremifene citrate, anastrazole, exemestane, letrozole,DES(diethylstilbestrol), estradiol, estrogen, conjugated estrogen,bevacizumab, IMC-1C11, CHIR-258);3-[5-(methylsulfonylpiperadinemethyl)-indolyl-quinolone, vatalanib,AG-013736, AVE-0005, goserelin acetate, leuprolide acetate, triptorelinpamoate, medroxyprogesterone acetate, hydroxyprogesterone caproate,megestrol acetate, raloxifene, bicalutamide, flutamide, nilutamide,megestrol acetate, CP-724714; TAK-165, HKI-272, erlotinib, lapatanib,canertinib, ABX-EGF antibody, erbitux, EKB-569, PKI-166, GW-572016,lonafarnib, BMS-214662, tipifarnib; amifostine, NVP-LAQ824, suberoylanalide hydroxamic acid, valproic acid, trichostatin A, FK-228, SU11248,sorafenib, KRN951, aminoglutethimide, arnsacrine, anagrelide,L-asparaginase, Bacillus Calmette-Guerin (BCG) vaccine, adriamycin,bleomycin, buserelin, busulfan, carboplatin, carmustine, chlorambucil,cisplatin, cladribine, clodronate, cyproterone, cytarabine, dacarbazine,dactinomycin, daunorubicin, diethylstilbestrol, epirubicin, fludarabine,fludrocortisone, fluoxymesterone, flutamide, gleevec, gemcitabine,hydroxyurea, idarubicin, ifosfamide, imatinib, leuprolide, levamisole,lomustine, mechlorethamine, melphalan, 6-mercaptopurine, mesna,methotrexate, mitomycin, mitotane, mitoxantrone, nilutamide, octreotide,oxaliplatin, pamidronate, pentostatin, plicamycin, porfimer,procarbazine, raltitrexed, rituximab, streptozocin, teniposide,testosterone, thalidomide, thioguanine, thiotepa, tretinoin, vindesine,13-cis-retinoic acid, phenylalanine mustard, uracil mustard,estramustine, altretamine, floxuridine, 5-deooxyuridine, cytosinearabinoside, 6-mecaptopurine, deoxycoformycin, calcitriol, valrubicin,mithramycin, vinblastine, vinorelbine, topotecan, razoxin, marimastat,COL-3, neovastat, BMS-275291, squalamine, endostatin, SU5416, SU6668,EMD121974, interleukin-12, IM862, angiostatin, vitaxin, droloxifene,idoxyfene, spironolactone, finasteride, cimitidine, trastuzumab,denileukin diftitox,gefitinib, bortezimib, paclitaxel, cremophor-freepaclitaxel, docetaxel, epithilone B, BMS-247550, BMS-310705,droloxifene, 4-hydroxytamoxifen, pipendoxifene, ERA-923, arzoxifene,fulvestrant, acolbifene, lasofoxifene, idoxifene, TSE-424, HMR-3339,ZK186619, topotecan, PTK787/ZK 222584, VX-745, PD 184352, rapamycin,40-O-(2-hydroxyethyl)-rapamycin, temsirolimus, AP-23573, RAD001,ABT-578, BC-210, LY294002, LY292223, LY292696, LY293684, LY293646,wortmannin, ZM336372, L-779,450, PEG-filgrastim, darbepoetin,erythropoietin, granulocyte colony-stimulating factor, zolendronate,prednisone, cetuximab, granulocyte macrophage colony-stimulating factor,histrelin, pegylated interferon alfa-2a, interferon alfa-2a, pegylatedinterferon alfa-2b, interferon alfa-2b, azacitidine, PEG-L-asparaginase,lenalidomide, gemtuzumab, hydrocortisone, interleukin-11, dexrazoxane,alemtuzumab, all-transretinoic acid, ketoconazole, interleukin-2,megestrol, immune globulin, nitrogen mustard, methylprednisolone,ibritgumomab tiuxetan, androgens, decitabine, hexamethylmelamine,bexarotene, tositumomab, arsenic trioxide, cortisone, editronate,mitotane, cyclosporine, liposomal daunorubicin, Edwina-asparaginase,strontium 89, casopitant, netupitant, an NK-1 receptor antagonist,palonosetron, aprepitant, diphenhydramine, hydroxyzine, metoclopramide,lorazepam, alprazolam, haloperidol, droperidol, dronabinol,dexamethasone, methylprednisolone, prochlorperazine, granisetron,ondansetron, dolasetron, tropisetron, pegfilgrastim, erythropoietin,epoetin alfa, darbepoetin alfa and mixtures thereof.

The term “anti-HIV agent” or “additional anti-HIV agent” includes, forexample, nucleoside reverse transcriptase inhibitors (NRTI), othernon-nucloeoside reverse transcriptase inhibitors (i.e., those which arenot representative of the present disclosure), protease inhibitors,fusion inhibitors, among others, exemplary compounds of which mayinclude, for example, 3TC (Lamivudine), AZT (Zidovudine), (−)-FTC, ddI(Didanosine), ddC (zalcitabine), abacavir (ABC), tenofovir (PMPA),D-D4FC (Reverset), D4T (Stavudine), Racivir, L-FddC, L-FD4C, NVP(Nevirapine), DLV (Delavirdine), EFV (Efavirenz), SQVM (Saquinavirmesylate), RTV (Ritonavir), IDV (Indinavir), SQV (Saquinavir), NFV(Nelfinavir), APV (Amprenavir), LPV (Lopinavir), fusion inhibitors suchas T20, among others, fuseon and mixtures thereof, including anti-HIVcompounds presently in clinical trials or in development.

Other anti-HIV agents which may be used in coadministration withcompounds according to the present disclosure include, for example,other NNRTI's (i.e., other than the NNRTI's according to the presentdisclosure) may be selected from the group consisting of nevirapine(BI-R6-587), delavirdine (U-90152S/T), efavirenz (DMP-266), UC-781(N-[4-chloro-3-(3-methyl-2-butenyloxy)phenyl]-2methyl3-furancarbothiamide),etravirine (TMC125), Trovirdine (Ly300046.HCl), MKC-442 (emivirine,coactinon), HI-236, HI-240, HI-280, HI-281, rilpivirine (TMC-278),MSC-127, HBY 097, DMP266, Baicalin (TJN-151) ADAM-II (Methyl3′,3′-dichloro-4′,4″-dimethoxy-5′,5″-bis(methoxycarbonyl)-6,6-diphenylhexenoate),Methyl3-Bromo-5-(1-5-bromo-4-methoxy-3-(methoxycarbonyl)phenyl)hept-1-enyl)-2-methoxybenzoate(Alkenyldiarylmethane analog, Adam analog),(5-chloro-3-(phenylsulfinyl)-2′-indolecarboxamide), AAP-BHAP (U-104489or PNU-104489), Capravirine (AG-1549, S-1153), atevirdine (U-87201E),aurin tricarboxylic acid (SD-095345),1-[(6-cyano-2-indolyl)carbonyl]-4-[3-(isopropylamino)-2-pyridinyl]piperazine,1-[5-[[N-(methyl)methylsulfonylamino]-2-indolylcarbonyl-4-[3-(isopropylamino)-2-pyridinyl]piperazine,1-[3-(Ethylamino)-2-[pyridinyl]-4-[(5-hydroxy-2-indolyl)carbonyl]piperazine,1-[(6-Formyl-2-indolyl)carbonyl]-4-[3-(isopropylamino)-2-pyridinyl]piperazine,1-[[5-(Methylsulfonyloxy)-2-indoyly)carbonyl]-4-[3-(isopropylamino)-2-pyridinyl]piperazine,U88204E, Bis(2-nitrophenyl)sulfone (NSC 633001), Calanolide A(NSC675451), Calanolide B,6-Benzyl-5-methyl-2-(cyclohexyloxy)pyrimidin-4-one (DABO—546), DPC 961,E-EBU, E-EBU-dm, E-EPSeU, E-EPU, Foscarnet (Foscavir), HEPT(1-[(2-Hydroxyethoxy)methyl]-6-(phenylthio)thymine), HEPT-M(1-[(2-Hydroxyethoxy)methyl]-6-(3-methylphenyl)thio)thymine),HEPT-S(1-[(2-Hydroxyethoxy)methyl]-6-(phenylthio)-2-thiothymine),Inophyllum P, L-737,126, Michellamine A (NSC650898), Michellamine B(NSC649324), Michellamine F,6-(3,5-Dimethylbenzyl)-1-[(2-hydroxyethoxy)methyl]-5-isopropyluracil,6-(3,5-Dimethylbenzyl)-1-(ethyoxymethyl)-5-isopropyluracil, NPPS, E-BPTU(NSC 648400), Oltipraz(4-Methyl-5-(pyrazinyl)-3H-1,2-dithiole-3-thione),N-{2-(2-Chloro-6-fluorophenethyl]-N′-(2-thiazolyl)thiourea (PETT Cl, Fderivative),N-{2-(2,6-Difluorophenethyl]-N′-[2-(5-bromopyridyl)]thiourea {PETTderivative), N-{2-(2,6-Difluorophenethyl]-N′—[2-(5-methylpyridyl)]thiourea {PETT Pyridyl derivative),N-[2-(3-Fluorofuranyl)ethyl]-N′-[2-(5-chloropyridyl)]thiourea,N-[2-(2-Fluoro-6-ethoxyphenethyl)]—N′— [2-(5-bromopyridyl)]thiourea,N-(2-Phenethyl)-N′-(2-thiazolyl)thiourea (LY-73497), L-697,639,L-697,593, L-697,661,3-[2-(4,7-Difluorobenzoxazol-2-yl)ethyl}-5-ethyl-6-methyl(pypridin-2(1H)-thione(2-Pyridinone Derivative),3-[[(2-Methoxy-5,6-dimethyl-3-pyridyl)methyl]amine]-5-ethyl-6-methyl(pypridin-2(1H)-thione,R82150, R82913, R87232, R88703, R89439 (Loviride), R90385, S-2720,Suramin Sodium, TBZ (Thiazolobenzimidazole, NSC 625487),Thiazoloisoindol-5-one,(+)(R)-9b-(3,5-Dimethylphenyl-2,3-dihydrothiazolo[2,3-a]isoindol-5(9bH)-one,Tivirapine (R86183), UC-38 and UC-84, among others.

The term “pharmaceutically acceptable salt” is used throughout thespecification to describe, where applicable, a salt form of one or moreof the compounds described herein which are presented to increase thesolubility of the compound in the gastic juices of the patient'sgastrointestinal tract in order to promote dissolution and thebioavailability of the compounds. Pharmaceutically acceptable saltsinclude those derived from pharmaceutically acceptable inorganic ororganic bases and acids, where applicable. Suitable salts include thosederived from alkali metals such as potassium and sodium, alkaline earthmetals such as calcium, magnesium and ammonium salts, among numerousother acids and bases well known in the pharmaceutical art. Sodium andpotassium salts are particularly preferred as neutralization salts ofthe phosphates according to the present disclosure.

The term “pharmaceutically acceptable derivative” is used throughout thespecification to describe any pharmaceutically acceptable prodrug form(such as an ester, amide other prodrug group), which, uponadministration to a patient, provides directly or indirectly the presentcompound or an active metabolite of the present compound.

General Synthetic Approach

The synthetic realization and optimization of the bifunctional moleculesas described herein may be approached in a step-wise or modular fashion.For example, identification of compounds that bind to the targetmolecules can involve high or medium throughput screening campaigns ifno suitable ligands are immediately available. It is not unusual forinitial ligands to require iterative design and optimization cycles toimprove suboptimal aspects as identified by data from suitable in vitroand pharmacological and/or ADMET assays. Part of the optimization/SARcampaign would be to probe positions of the ligand that are tolerant ofsubstitution and that might be suitable places on which to attach thelinker chemistry previously referred to herein. Where crystallographicor NMR structural data are available, these can be used to focus such asynthetic effort.

In a very analogous way one can identify and optimize ligands for an E3Ligase, i.e. ULMs/ILMs/VLMs/CLMs/ILMs.

With PTMs and ULMs (e.g. ILMs, VLMs, CLMs, and/or ILMs) in hand, oneskilled in the art can use known synthetic methods for their combinationwith or without a linker moiety. Linker moieties can be synthesized witha range of compositions, lengths and flexibility and functionalized suchthat the PTM and ULM groups can be attached sequentially to distal endsof the linker. Thus a library of bifunctional molecules can be realizedand profiled in in vitro and in vivo pharmacological and ADMET/PKstudies. As with the PTM and ULM groups, the final bifunctionalmolecules can be subject to iterative design and optimization cycles inorder to identify molecules with desirable properties.

In some instances, protecting group strategies and/or functional groupinterconversions (FGIs) may be required to facilitate the preparation ofthe desired materials. Such chemical processes are well known to thesynthetic organic chemist and many of these may be found in texts suchas “Greene's Protective Groups in Organic Synthesis” Peter G. M. Wutsand Theodora W. Greene (Wiley), and “Organic Synthesis: TheDisconnection Approach” Stuart Warren and Paul Wyatt (Wiley).

Abbreviations

AcOH acetic acid

AcONa sodium acetate

Boc tert-butyloxycarbonyl

(Boc)₂O di-tert-butyl dicarbonate

CDCl₃ chloroform-d

DCE 1,2-dichloroethane

DCM dichloromethane

DIAD Diisopropyl azodicarboxylate

DIBAL-H diisobutylaluminium hydride

DIEA N,N-diisopropylethylamine

DMA N,N-dimethylacetamide

DMAP 4-dimethylaminopyridine

DMF N,N-dimethylformamide

DMP Dess-Martin periodinane

DMSO dimethyl sulfoxide

EDCI 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide

eq equivalent(s)

EtOAc ethyl acetate

EtOH ethyl alcohol

h hour(s)

HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxide hexafluorophosphate

HCl hydrochloric acid

HOBt hydroxybenzotriazole

HPLC high performance liquid chromatography

MeCN acetonitrile

MeOH methanol

M.W. microwave

NaHCO₃ sodium bicarbonate

NMR nuclear magnetic resonance

OMs mesylate

OTs tosylate

Pd/C palladium on carbon

Pd(PPh₃)₄ tetrakis(triphenylphosphine)palladium(O)

PhSO₃H benzenesulfonic acid

PPTS pyridinium p-toluenesulfonate

Rf retention factor

TEA triethylamine

TFA trifluoroacetic acid

THF tetrahydrofuran

TLC thin-layer chromatography

TosCl 4-toluenesulfonyl chloride

INTERMEDIATES Intermediate 1: ethyl(1s,4s)-4-aminocyclohexanecarboxylate

To a solution of (1s,4s)-4-aminocyclohexanecarboxylic acid (10 g, 69.84mmol, 1 eq) in ethyl alcohol (100 mL) was added thionyl chloride (41.54g, 349.20 mmol, 25.33 mL, 5 eq) at 0° C. The reaction mixture was heatedto 65° C. and allowed to stir for 3 hours. ¹H NMR spectroscopy showeddesired compound was detected. The reaction mixture was concentratedunder reduced pressure. The crude product was triturated with ethylacetate (50 mL). Ethyl (1s,4s)-4-aminocyclohexanecarboxylate (13.8 g,66.44 mmol, 95% yield, hydrochloride) was obtained as a white solid. ¹HNMR (400 MHz, DMSO-d₆) δ: 8.16 (s, 3H), 4.08 (q, J=7.2 Hz, 2H), 3.04 (d,J=4.4 Hz, 1H), 2.62-2 .53 (m, 1H), 2.02-1.90 (m, 2H), 1.79 (dd, J=4.4,10.0 Hz, 2H), 1.63-1.41 (m, 4H), 1.14 (s, 1H), 1.19 (t, J=7.12 Hz, 2H).

Intermediate 2: 2-(2,6-dioxo-3-piperidyl)-5-fluoro-isoindoline-1,3-dione

To a solution of 5-fluoroisobenzofuran-1,3-dione (1.00 g, 6.02 mmol,1.00 eq) in acetic acid (10 mL) was added sodium acetate (987 mg, 12.04mmol, 2.00 eq) and 3-aminopiperidine-2,6-dione (2.97 g, 18.06 mmol, 3.00eq, hydrochloric acid). The mixture was stirred at 115° C. for 6 hours.LCMS analysis of the crude reaction mixture indicated completeconversion. The reaction mixture was washed with water (20 mL). Themixture was filtered and concentrated under reduced pressure to afford2-(2,6-dioxo-3-piperidyl)-5-fluoro-isoindoline-1,3-dione (1.20 g, 4.34mmol, 72% yield) as a black solid. MS (ESI) m/z: 277.0 [M+H]⁺. ¹H NMR(400 MHz, DMSO-d₆) δ: 11.16 (s, 1H), 8.02 (dd, J=3.6, 4.4 Hz, 1H), 7.86(dd, J=2.4, 7.6 Hz, 1H) 7.65-7.79 (m, 1H), 5.17 (dd, J=5.2, 12.8 Hz,1H), 2.80-2.96 (m, 1H), 2.53-2.71 (m, 2H), 2.00-2.13 (m, 1H).

Intermediate 3: tert-buty-N-methyl-N-[2-(2-oxoethoxy) ethyl]carbamate

Step 1:

A solution of 2-(2-hydroxyethoxy)ethyl 4-methylbenzenesulfonate (2.50 g,9.60 mmol, 1 eq) and methanamine (40.0 mL, 1.00 eq) in sealed tube wasstirred at 70° C. for 12 hours. Analysis by TLC indicated2-(2-hydroxyethoxy)ethyl 4-methylbenzenesulfonate was consumedcompletely. The reaction mixture was concentrated under reduced pressureto remove methanamine (40.0 mL, 1.00 eq) to give2-[2-(methylamino)ethoxy]ethanol (1.10 g, crude) as a yellow oil.

Step 2:

To a solution of 2-[2-(methylamino)ethoxy]ethanol (1.10 g, 9.23 mmol,1.00 eq) in tetrahydrofuran (20.0 mL) and water (10.0 mL) was addeddi-tert-butyldicarbonate (3.02 g, 13.85 mmol, 3.2 mL, 1.50 eq) andsodium bicarbonate (1.55 g, 18.46 mmol, 0.7 mL, 2.00 eq). The mixturewas stirred at 70° C. for 10 hours. Analysis by TLC and LCMS indicatedthe reaction was complete. The reaction mixture was quenched by additionof water (100 mL) and extracted with ethyl acetate (100 mL×2). Thecombined organic layers were concentrated under reduced pressure to givea residue. The residue was purified by column chromatography to givetert-butyl N-[2-(2-hydroxyethoxy)ethyl]-N-methyl-carbamate (400 mg, 1.82mmol, 19% yield) as a yellow oil. MS (ESI) m/z: 219.9 [M+H]⁺. ¹H NMR(400 MHz, CDCl₃) δ: 3.79-3.68 (m, 2H), 3.65-3.54 (m, 4H), 3.50-3.27 (m,2H), 2.98-2.85 (m, 3H), 1.49-1.37 (m, 9H).

Step 3:

To a solution of tert-butylN-[2-(2-hydroxyethoxy)ethyl]-N-methyl-carbamate (100 mg, 0.46 mmol, 1.00eq) in dichloromethane (3.0 mL) was added(1,1,1-triacetoxy)-1,1-dihydro-1,2-benziodoxol-3(1H)-one (232 mg, 0.55mmol, 0.2 mL, 1.20 eq). The mixture was stirred at 25° C. for 10 hours.The reaction mixture was concentrated under reduced pressure to removedichloromethane (3.0 mL) to give tert-butylN-methyl-N-[2-(2-oxoethoxy)ethyl]carbamate (60 mg, crude) as a yellowoil.

Intermediate 4: pyrazolo[1,5-a]pyrimidine-3-carbonyl chloride

To a solution of pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (200 mg,1.23 mmol, 1 eq) in dichloromethane (8 mL) was added oxalyl chloride(326 mg, 2.57 mmol, 2.1 eq) in dichloromethane (1.3 mL) andN,N-dimethylformamide (0.02 mL) at 0° C. The mixture was stirred at 20°C. for 1 hour. Thin layer chromatography (dichloromethane:methanol=10:1)showed the reaction was complete. The mixture was concentrated underreduced pressure to afford pyrazolo[1,5-a]pyrimidine-3-carbonyl chloride(200 mg, 1.10 mmol, 89% yield) as a brown solid and which was used inthe next step without further purification.

Intermediate 5: benzyl 4-(4-aminocyclohexyl)piperazine-1-carboxylate

Step 1:

To a solution of tert-butyl N-(4-oxocyclohexyl)carbamate (10 g, 46.89mmol, 1 eq) in methanol (150 mL) was added acetic acid (15 mL) andbenzyl piperazine-1-carboxylate (10.33 g, 46.89 mmol, 1 eq). The mixturewas stirred at 30° C. for 0.5 hour. Then 2-methylpyridine borane complex(10.03 g, 93.78 mmol, 2 eq) was added and the mixture was stirred at 30°C. for 12 hours. LCMS analysis of an aliquot indicated completion of thereaction. The reaction mixture was diluted with water (500 mL) andextracted with ethyl acetate (200 mL×3). The combined organic phase waswashed with a saturated aqueous solution of sodium bicarbonate (200 mL)and saturated brine (300 mL×2), dried with anhydrous sodium sulfate,filtered and concentrated under reduced pressure. The residue wastriturated with petroleum ether:ethyl acetate (V/V=5:1, 150 mL) to givebenzyl4-[4-(tert-butoxycarbonylamino)cyclohexyl]piperazine-1-carboxylate (13g, 31.1 mmol, 66.4% yield) obtained as a white solid. MS (ESI) m/z:418.2[M+H]⁺.

Step 2:

To a solution of benzyl4-[4-(tert-butoxycarbonylamino)cyclohexyl]piperazine-1-carboxylate (13g, 31.13 mmol, 1 eq) in dichloromethane (100 mL) was added hydrochloricacid in dioxane (100 mL). The mixture was stirred at 25° C. for 10minutes. Thin layer chromatography (petroleum ether: ethyl acetate=1:1)confirmed completion of the reaction. The mixture was concentrated underreduced pressure and the resulting residue was used in a subsequenttransformation without further purification. Compound benzyl4-(4-aminocyclohexyl)piperazine-1-carboxylate (10.9 g, 30.80 mmol, 98%yield, hydrochloride) was obtained as a white solid.

Intermediate 6: tert-butylN-[4-(4-vinylsulfonylpiperazin-1-yl)cyclohexyl]carbamate

Step 1:

To a solution of benzyl4-[4-(tert-butoxycarbonylamino)cyclohexyl]piperazine-1-carboxylate (7 g,16.76 mmol, 1 eq) in tetrahydrofuran (20 mL) and methanol (50 mL) wasadded palladium on activated carbon catalyst (700 mg, 16.73 mmol, 10%purity, 9.98e−1 eq) under nitrogen. The suspension was degassed undervacuum and purged with an atmosphere of hydrogen several times. Themixture was stirred under hydrogen (15 psi) at 25° C. for 12 hours. Thinlayer chromatography (petroleum ether: ethyl acetate=10:1) showed thereaction was complete. The mixture was filtered and concentrated underreduced pressure. The crude product was used in the next step withoutfurther purification. Compound tert-butyl N-(4-piperazin-1-ylcyclohexyl)carbamate (4.6 g, 16.23 mmol, 96% yield) was obtained as a white solid.¹H NMR: (400 MHz, DMSO-d₆) δ: 6.80-6.60 (m, 1H), 3.18-3.16 (m, 1H),2.69-2.60 (m, 4H), 2.40-2.31 (m, 4H), 2.07 (t, J=8.7 Hz, 1H), 1.79 (brs, 1H), 1.74 (br d, J=14.5 Hz, 2H), 1.70-1.53 (m, 2H), 1.46-1.38 (m,2H), 1.38-1.36 (m, 9H), 1.23-1.11 (m, 2H).

Step 2:

To a solution of tert-butyl N-(4-piperazin-1-ylcyclohexyl)carbamate (4.6g, 16.23 mmol, 1 eq) in dichloromethane (90 mL) was added triethylamine(8.21 g, 81.15 mmol, 5 eq) and 2-chloroethanesulfonyl chloride (3.97 g,24.35 mmol, 2.54 mL, 1.5 eq) at 0° C. The mixture was stirred at 25° C.for 2 hours. The mixture was concentrated under reduced pressure. Thecrude product was purified by silica gel column chromatography(petroleum ether: ethyl acetate=5:1 to 1:1) to give tert-butylN-[4-(4-vinylsulfonylpiperazin-1-yl)cyclohexyl]carbamate (2.4 g, 6.43mmol, 39% yield) as a brown solid. ¹H NMR: (400 MHz, DMSO-d₆) δ:6.86-6.74 (m, 1H), 6.21-6.05 (m, 2H), 3.54-3.41 (m, 1H), 3.22-3.05 (m,1H), 3.03-2.93 (m, 4H), 2.59-2.52 (m, 4H), 2.29-2.14 (m, 1H), 1.85-1.56(m, 4H), 1.47-1.38 (m, 2H), 1.38-1.31 (m, 9H), 1.26-1.15 (m, 2H).

Intermediate 7: 2-[2-(2-oxoethoxy)ethoxy]ethyl 4-methylbenzenesulfonate

To a solution of 2-[2-(2-hydroxyethoxy)ethoxy]ethyl4-methylbenzenesulfonate (4 g, 13.14 mmol, 1 eq) in DCM (80 mL) wasadded Dess-Martin periodinane (7.25 g, 17.10 mmol, 5.29 mL, 1.3 eq) andsodium bicarbonate (11.04 g, 131.42 mmol, 5.11 mL, 10 eq). The mixturewas stirred at 23° C. for 1 hour. LCMS analysis confirmed the reactionto be complete. The reaction mixture was poured into water (150 mL) at0° C. The mixture was extracted with dichloromethane (100 mL×2). Thecombined organic layers were washed with brine (100 mL×3), dried overanhydrous sodium sulfate, concentrated under vacuum and the resultingresidue was purified by column chromatography (petroleum ether/ethylacetate=10:1 to 0.25:1) to afford2-[2-(2-oxoethoxy)ethoxy]ethyl4-methylbenzenesulfonate (1.4 g, 4.63mmol, 35.23% yield) as a yellow oil. MS (ESI) m/z: 303.2 [M+H]⁺.

Intermediate 8:2-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]oxyacetaldehyde

Step 1:

The mixture of 2-(2,6-dioxo-3-piperidyl)-5-hydroxy-isoindoline-1,3-dione(1 g, 3.65 mmol, 1 eq) and potassium carbonate (1.01 g, 7.29 mmol, 2 eq)in dimethylformamide (10 mL) was degassed and refilled with nitrogen 3times, after which 3-bromoprop-1-ene (470 mg, 3.89 mmol, 1.1 eq) wasadded to the mixture. The mixture was stirred at 50° C. for 12 hours.The reaction mixture was quenched with water (60 mL) at 0° C., thenextracted with ethyl acetate (30 mL×3). The combined organic layers werewashed with brine (20 mL×2), dried over anhydrous sodium sulfate,filtered and concentrated to give a residue. The residue was purified bysilica gel column chromatography (petroleum ether/ethyl acetate=4/1 to1/1), to afford5-allyloxy-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione (0.9 g, 79%yield) obtained as a yellow solid. MS (ESI) m/z: 315.1 [M+H]⁺.

Step 2:

To the mixture of5-allyloxy-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione (0.7 g, 2.23mmol, 1 eq) in dichloromethane (200 mL) was bubbled ozone until themixture turned blue at −78° C. Then nitrogen was bubbled until thesolution became colorless. Dimethylsulfide (7.61 g, 123 mmol, 9 mL, 55eq) was added to the mixture at −78° C. under a nitrogen atmosphere. Themixture was stirred at 25° C. for 12 hours. The reaction mixture wasconcentrated to give a residue which was purified by silica gel columnchromatography (petroleum ether/ethyl acetate=1/1 to 0/1) to afford2-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]oxyacetaldehyde(0.7 g, crude), obtained as a light yellow solid. MS (ESI) m/z: 317.0[M+H]⁺.

Intermediate 9:2-[2-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]oxyethoxy]acetaldehyde

Step 1:

To a mixture of2-(2,6-dioxo-3-piperidyl)-5-hydroxy-isoindoline-1,3-dione (2 g, 7.29mmol, 1 eq) and potassium carbonate (3.02 g, 21.9 mmol, 3 eq) indimethylformamide (10 mL) was added 2-(2-hydroxyethoxy)ethyl4-methylbenzenesulfonate (2.09 g, 8.02 mmol, 1.1 eq). The mixture wasstirred at 50° C. for 12 hours. The reaction mixture was concentrated togive a residue. The residue was purified by silica gel columnchromatography (eluted with petroleum ether/ethyl acetate=1/1 to 0:1) toafford2-(2,6-dioxo-3-piperidyl)-5-[2-(2-hydroxyethoxy)ethoxy]isoindoline-1,3-dione(1.5 g, 54% yield), obtained as a yellow solid. MS (ESI) m/z: 362.9[M+H]⁺.

Step 2:

To a solution of2-(2,6-dioxo-3-piperidyl)-5-[2-(2-hydroxyethoxy)ethoxy]isoindoline-1,3-dione(500 mg, 1.38 mmol, 1 eq) in dichloromethane (20 mL) was added sodiumbicarbonate (1.16 g, 13.8 mmol, 0.54 mL, 10 eq), and Dess-Martinperiodinane (877 mg, 2 mmol, 1.5 eq) at 0° C. The mixture was stirred at25° C. for 1 hour. The reaction mixture was quenched with a solutioncomprised of 50 mL of a saturated aqueous solution of sodium bicarbonatesolution and 50 mL of an aqueous sodium thiosulfate solution. Themixture was then extracted with dichloromethane (30 mL×3). The combinedorganic phase was washed with brine 30 mL, dried over anhydrous sodiumsulfate, filtered and concentrated under vacuum. The resulting residuewas purified by silica gel chromatography (petroleum ether/ethylacetate=3/1 to 0/1), to afford crude2-[2-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]oxyethoxy]acetaldehyde(400 mg, 80% yield), obtained as a colorless oil.

Intermediate 10:2-[2-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]oxyethoxy]ethyl4-methylbenzenesulfonate

To a solution of2-(2,6-dioxo-3-piperidyl)-5-[2-(2-hydroxyethoxy)ethoxy]isoindoline-1,3-dione,Intermediate 9 (400 mg, 1.10 mmol, 1 eq) in dichloromethane (5 mL) wasadded para-toluenesulfonyl chloride (315 mg, 1.66 mmol, 1.5 eq),4-dimethylaminopyridine (13 mg, 0.11 mmol, 0.1 eq) and triethylamine(335 mg, 3.31 mmol, 3 eq). The mixture was stirred at 25° C. for 12hours. LCMS analysis confirmed the reaction to be complete. The mixturewas diluted with water (10 mL) and extracted with dichloromethane (10mL×3). The combined organic layers were washed with brine (20 mL×2),dried with anhydrous sodium sulfate, filtered and concentrated underreduced pressure. The residue was purified by preparative reverse phasethin layer chromatography (dichloromethane:methanol=20:1) to give2-[2-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]oxyethoxy]ethyl4-methylbenzenesulfonate (150 mg, 0.29 mmol, 26% yield) as a colorlessoil. MS (ESI) m/z: 517.1[M+H]⁺.

Intermediate 11: 3-hydroxy-4-methoxybenzenesulfonic acid

Step 1:

To a solution of sodium hydroxide (80 g, 2.00 mol, 4.97 eq) in water(500 mL) was added 2-methoxyphenol (50 g, 402.78 mmol, 45.05 mL, 1 eq)at 0° C., and then benzoyl chloride (65 g, 462.41 mmol, 53.72 mL, 1.15eq) was added to above solution. The mixture was stirred at 0-25° C. for1 hour. The reaction mixture was filtered to afford crude2-methoxyphenyl benzoate (54 g, 236.59 mmol, 59% yield, 100% purity) asa white solid which was used in the next step without furtherpurification. MS (ESI) m/z: 229.1 [M+H]⁺.

Step 2:

To a solution of 2-methoxyphenyl benzoate (100 g, 438.13 mmol, 1 eq) indichloromethane (1000 mL) was added chlorosulfonic acid (51 g, 437.68mmol, 29.14 mL, 0.99 eq) at 0° C. The mixture was stirred at 0° C. for 3hours. The reaction mixture was filtered and the cake was collected toprovide crude product 3-(benzoyloxy)-4-methoxybenzenesulfonic acid (95g, 308.14 mmol, 70% yield) as a white solid which was used into the nextstep without further purification. ¹H NMR (400 MHz, DMSO-d₆) δ=8.15-8.09(m, 2H), 7.78-7.71 (m, 1H), 7.64-7.57 (m, 2H), 7.55 (dd, J=2.0, 8.4 Hz,1H), 7.40 (d, J=2.0 Hz, 1H), 6.26 (br d, J=16.8 Hz, 5H), 3.76 (s, 3H).

Step 3:

To a solution of 3-(benzoyloxy)-4-methoxybenzenesulfonic acid (90 g,291.92 mmol, 1 eq) in methanol (450 mL) was added potassium hydroxide(60 g, 1.07 mol, 3.66 eq) in water (450 mL) at 0° C., and then themixture was stirred at 25° C. for 10 hours. The reaction mixture wasconcentrated under reduced pressure to remove methanol. The residue wasdiluted with water (100 mL) and the pH was adjusted to 7 with theaddition of a concentrated aqueous solution of hydrochloric acid. Themixture was then extracted with ethyl acetate (100 mL×6). The aqueouslayer was concentrated under reduced pressure to give a residue. Theresidue was washed with ethanol 100 mL, filtered and concentrated underreduced pressure to afford 3-hydroxy-4-methoxybenzenesulfonic acid (50g, 244.86 mmol, 84% yield) as a brown oil. ¹H NMR (400 MHz, DMSO-d₆)δ=7.07 (d, J=2.0 Hz, 1H), 7.02 (dd, J=2.0, 8.0 Hz, 1H), 6.84 (d, J=8.4Hz, 1H), 5.81 (br s, 5H), 3.75 (s, 3H).

A compound of formula I may be reacted with a reagent II (commerciallyavailable or readily prepared using standard reaction techniques knownto one skilled in the art) where Z is an appropriate leaving group (e.g.OMs, OTs, Cl, Br, etc.) under O— alkylation conditions to produce acompound of formula III, wherein L represents an optional linker orportion of a linker and X is CH₂ or C═O. Suitable reactions conditionsfor O-alkylation entail the use of a base, e.g. NaH or potassiumcarbonate in a solvent such as DMF at 60° C. Compounds of formula IIImay react with a compound of formula IV through N-alkylation where Y isan appropriate leaving group (e.g. OMs, OTs, Cl, etc.) or throughreductive amination where Y is an aldehyde to produce compound offormula V. When Y is a leaving group, suitable reaction conditions arethose for an alkylation reaction, e.g. diisopropylethylamine, potassiumiodide, DMSO or acetonitrile, 80° C. When Y is an aldehyde, suitablereaction conditions are those for a reductive amination reaction, e.g.sodium cyanoborohydride, methanol, dichloromethane, acetic acid, roomtemperature.

Exemplary Synthesis of Exemplary Compound 1N-(5-((4-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)ethyl)piperazin-1-yl)methyl)-1-((1s,4s)-4-(hydroxymethyl)cyclohexyl)-1H-benzo[d]imidazol-2-yl)-3-(trifluoromethyl)benzamide

Step 1:

To a solution of (4-fluoro-3-nitro-phenyl)methanol (10 g, 58.44 mmol, 1eq) in tetrahydrofuran (100 mL) was added pyridinium p-toluenesulfonate(1.47 g, 5.84 mmol, 0.1 eq) and 2,3-dihydropyrane (14.75 g, 175.31 mmol,16 mL, 3 eq). The mixture was stirred at 25° C. for 12 hours. LCMSanalysis showed the reaction was complete. The reaction mixture wasdiluted with water (300 mL) and extracted with ethyl acetate (100 mL×2).The combined organic phase was washed with saturated brine (100 mL×2),dried with anhydrous sodium sulfate, filtered and concentrated underreduced pressure to give a residue. The residue was purified by silicagel chromatography eluting with a gradient from 20:1 to 10:1 petroleumether:ethyl acetate to afford2-[(4-fluoro-3-nitro-phenyl)methoxy]tetrahydropyran (14 g, 54.8 mmol,93% yield) as a light yellow solid.

Step 2:

To a solution of 2-[(4-fluoro-3-nitro-phenyl)methoxy]tetrahydropyran (14g, 54.8 mmol, 1 eq) in dimethylsulfoxide (150 mL) was addeddiisopropylethylamine (28.36 g, 219.4 mmol, 38.2 mL, 4 eq) and ethyl(1s,4s)-4-aminocyclohexanecarboxylate, Intermediate 1 (11.39 g, 54.85mmol, 1 eq, hydrochloride). The mixture was stirred at 110° C. for 12hours. Thin layer chromatography (petroleum ether: ethyl acetate=1:1)confirmed the reaction to be complete. The reaction mixture was dilutedwith water (300 mL) and extracted with ethyl acetate (150 mL×2). Thecombined organic phase was washed with saturated brine (100 mL×2), driedwith anhydrous sodium sulfate, filtered and concentrated under reducedpressure. The residue was purified by silica gel chromatography elutingwith a gradient from 10:1 to 5:1 petroleum ether:ethyl acetate to giveethyl(1s,4s)-4-[2-nitro-4-(tetrahydropyran-2-yloxymethyl)anilino]cyclohexanecarboxylate(22 g, 54.12 mmol, 98% yield) as a yellow solid.

¹H NMR (400 MHz, CDCl₃) δ: 8.26 (d, J=7.2 Hz, 1H), 8.17 (d, J=1.2 Hz,1H), 7.44 (dd, J=1.6, 8.8 Hz, 1H), 6.85 (d, J=8.8 Hz, 1H), 4.73-4 .62(m, 2H), 4.38 (d, J=11.6 Hz, 1H), 4.16 (q, J=7.2 Hz, 2H), 3.90 (ddd,J=2.8, 8.4, 11.2 Hz, 1H), 3.71 (s, 1H), 3.60-3.49 (m, 1H), 2.58-2.44 (m,1H), 2.03-1.93 (m, 2H), 1.90-1.73 (m, 8H), 1.66-1.51 (m, 4H), 1.27 (t,J=7.2 Hz, 3H).

Step 3:

To a solution of ethyl(1s,4s)-4-[2-nitro-4-(tetrahydropyran-2-yloxymethyl)anilino]cyclohexanecarboxylate(22 g, 54.12 mmol, 1 eq) in ethyl alcohol (250 mL) was added palladiumon activated carbon catalyst (2 g, 10% purity) under nitrogenatmosphere. The suspension was degassed and purged with an atmosphere ofhydrogen 3 times. The mixture was stirred under hydrogen (15 psi) at 25°C. for 12 hours. Thin layer chromatography (petroleum ether: ethylacetate=1:1) showed the reaction was complete. The reaction mixture wasfiltered and the filtrate was concentrated to afford ethyl(1s,4s)-4-[2-amino-4-(tetrahydropyran-2-yloxymethyl)anilino]cyclohexanecarboxylate (20 g, 53.12 mmol, 98% yield) as a brown oilwhich was used in the subsequent reaction without further purification.

Step 4:

To a solution of ethyl(1s,4s)-4-[2-amino-4-(tetrahydropyran-2-yloxymethyl)anilino]cyclohexanecarboxylate(10 g, 26.56 mmol, 1 eq) in methanol (100 mL) was added a solution ofcyanogen bromide (3.38 g, 31.87 mmol, 1.2 eq) in acetonitrile (5.2 mL)and water (5.2 mL) dropwise. The mixture was stirred at 50° C. for 12hours. LCMS analysis of the reaction mixture indicated the reaction wascomplete. The pH of the reaction mixture was adjusted to between 9 and10 with a saturated aqueous solution of sodium bicarbonate. The mixturewas diluted with water (200 mL) and extracted with ethyl acetate (80mL×3). The combined organic phase was washed with a saturated aqueoussolution of brine (120 mL×2), dried with anhydrous sodium sulfate,filtered and concentrated under vacuum. The residue was triturated withethyl acetate (80 mL) to afford ethyl(1s,4s)-4-[2-amino-5-(hydroxymethyl)benzimidazol-1-yl]cyclohexanecarboxylate(8.2 g, 25.84 mmol, 97% yield) as a brown solid. MS (ESI) m/z: 318.1[M+H]+.

Step 5:

To a solution of ethyl(1s,4s)-4-[2-amino-5-(hydroxymethyl)benzimidazol-1-yl]cyclohexanecarboxylate(5.00 g, 15.75 mmol, 1 eq) and 3-(trifluoromethyl)benzoic acid (3.00 g,15.75 mmol, 1 eq) in dimethylformamide (80 mL) was addedhydroxybenzotriazole (2.55 g, 18.90 mmol, 1.2 eq) and triethylamine(3.19 g, 31.51 mmol, 4.4 mL, 2 eq). The mixture was stirred at 25° C.for 0.5 hour, after which 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (4.53 g, 23.63 mmol, 1.5 eq) was added, and the mixturewas stirred at 25° C. for 1.5 hours. LCMS analysis of the reactionmixture showed the reaction was complete. The reaction mixture wasdiluted with water (300 mL) and extracted with ethyl acetate (100 mL×3).The combined organic phase was washed with a saturated aqueous brinesolution (150 mL×3), dried with anhydrous sodium sulfate, filtered andconcentrated under reduced pressure. The residue was purified by silicagel chromatography (petroleum ether: ethyl acetate=10:1 to 2:1) to giveethyl(1s,4s)-4-[5-(hydroxymethyl)-2-[[3-(trifluoromethyl)benzoyl]amino]benzimidazol-1-yl]cyclohexanecarboxylate(2.5 g, 5.11 mmol, 32% yield) as a pink solid. MS (ESI) m/z: 490.0[M+H]+.

Step 6:

To a solution of ethyl(1s,4s)-4-[5-(hydroxymethyl)-2-[[3-(trifluoromethyl)benzoyl]amino]benzimidazol-1-yl]cyclohexanecarboxylate(300 mg, 0.61 mmol, 1 eq) in dichloromethane (15 mL) was addedDess-Martin periodinane (312 mg, 0.73 mmol, 1.2 eq). The mixture wasstirred at 25° C. for 2 hours. Thin layer chromatography (petroleumether: ethyl acetate=1:1) showed the reaction was complete. The reactionmixture was filtered and the filtrate was adjusted to a pH between 8 and9 with the addition of a saturated aqueous solution of sodiumbicarbonate. The mixture was diluted with water (20 mL) and extractedwith dichloromethane (10 mL×3). The combined organic phase was washedwith a saturated aqueous brine solution (15 mL×2), dried with anhydroussodium sulfate, filtered and concentrated under reduced pressure. Theresidue was purified by silica gel chromatography (petroleum ether:ethyl acetate=30:1 to 10:1) to give ethyl(1s,4s)-4-[5-formyl-2-[[3-(trifluoromethyl)benzoyl]amino]benzimidazol-1-yl]cyclohexanecarboxylate(260 mg, 0.53 mmol, 87% yield) as a purple solid.

Step 7:

To a solution of tert-butyl piperazine-1-carboxylate (714 mg, 3.84 mmol,1.1 eq) in 1,2-dichloroethane (20 mL) was added ethyl(1s,4s)-4-[5-formyl-2-[[3-(trifluoromethyl)benzoyl]amino]benzimidazol-1-yl]cyclohexanecarboxylate(1.7 g, 3.49 mmol, 1 eq) and triethylamine (1.46 mL, 3 eq). The mixturewas stirred at 25° C. for 0.5 hour. Sodium triacetoxyborohydride (1.48g, 6.97 mmol, 2 eq) was added, then the mixture was stirred at 25° C.for 1.5 hours. LCMS analysis of the crude reaction mixture showed thereaction was complete. The reaction mixture was diluted with water (50mL) and extracted with dichloromethane (30 mL×2). The combined organicphase was washed with a saturated brine solution (30 mL×2), dried withanhydrous sodium sulfate, filtered and concentrated. The residue waspurified by silica gel chromatography (petroleum ether: ethylacetate=10:1 to 2:1) to give tert-butyl4-((1-((1s,4s)-4-(ethoxycarbonyl)cyclohexyl)-2-(3-(trifluoromethyl)benzamido)-1H-benzimidazol-5-yl)methyl)piperazine-1-carboxylate(1.3 g, 1.98 mmol, 56% yield) as a white solid. MS (ESI) m/z: 658.3[M+H]⁺.

Step 8:

To a solution of tert-butyl4-((1-((1s,4s)-4-(ethoxycarbonyl)cyclohexyl)-2-(3-(trifluoromethyl)benzamido)-1H-benzimidazol-5-yl)methyl)piperazine-1-carboxylate(1.1 g, 1.67 mmol, 1 eq) in tetrahydrofuran (30 mL) was added lithiumaluminum hydride (126 mg, 3.34 mmol, 2 eq) at 0° C. The mixture wasstirred at 0° C. for 10 minutes. LCMS analysis of the crude reactionmixture showed the conversion was complete. The reaction mixture wasquenched with water (3 mL) at 0° C. and anhydrous sodium sulfate (15 g)was added. The mixture was stirred at 25° C. for 15 minutes and was thenfiltered. The filtrate was concentrated and the resulting residue waspurified by silica gel chromatography (petroleum ether: ethylacetate=2:1 to 1:4) to give tert-butyl4-((1-((1s,4s)-4-(hydroxymethyl)cyclohexyl)-2-(3-(trifluoromethyl)benzamido)-1H-benzo[d]imidazol-5-yl)methyl)piperazine-1-carboxylate(380 mg, 0.61 mmol, 36% yield) as a white solid. MS (ESI) m/z: 616.2[M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ: 12.59 (s, 1H), 8.60 (s, 1H), 8.48 (d,J=8.0 Hz, 1H), 7.75 (d, J=8.0 Hz, 1H), 7.64-7.54 (m, 1H), 7.36-7.30 (m,2H), 7.22 (dd, J=1.2, 8.4 Hz, 1H), 4.76-4.63 (m, 1H), 3.96 (d, J=7.2 Hz,2H), 3.58 (s, 2H), 3.49-3.38 (m, 4H), 2.67-2.51 (m, 2H), 2.40 (t, J=5.2Hz, 4H), 2.12-2.05 (m, 3H), 1.84-1.75 (m, 4H), 1.73-1.71 (m, 1H), 1.46(s, 9H).

Step 9:

To a solution of tert-butyl4-((1-((1s,4s)-4-(hydroxymethyl)cyclohexyl)-2-(3-(trifluoromethyl)benzamido)-1H-benzo[d]imidazol-5-yl)methyl)piperazine-1-carboxylate(430 mg, 0.69 mmol, 1 eq) in dichloromethane (5 mL) was added 4 Mhydrochloric acid in dioxane (4 M, 5 mL, 28.6 eq). The mixture wasstirred at 25° C. for 1 hour. LCMS analysis of the crude reactionmixture showed the reaction was complete. The reaction mixture wasconcentrated under reduced pressure to remove dioxane. The residue wasdiluted with water (10 mL) and pH was adjusted to between 9 and 10 witha saturated aqueous solution of sodium bicarbonate. The mixture wasextracted with ethyl acetate (10 mL×2). The combined organic phase waswashed with a saturated brine solution (10 mL×2), dried with anhydroussodium sulfate, filtered and concentrated to giveN-(1-((1s,4s)-4-(hydroxymethyl)cyclohexyl)-5-(piperazin-1-ylmethyl)-1H-benzo[d]imidazol-2-yl)-3-(trifluoromethyl)benzamide(310 mg, 0.60 mmol, 86% yield) as a white solid. MS (ESI) m/z: 516.2[M+H]⁺.

Step 10:

To a solution ofN-(1-((1s,4s)-4-(hydroxymethyl)cyclohexyl)-5-(piperazin-1-ylmethyl)-1H-benzo[d]imidazol-2-yl)-3-(trifluoromethyl)benzamide(40 mg, 77.58 umol, 1 eq) in 1,2-dichloroethane (3 mL) was addedtriethylamine (23 mg, 0.23 mmol, 3 eq) and2-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]oxyacetaldehyde,Intermediate 8 (49 mg, 0.15 mmol, 2 eq). The mixture was stirred at 25°C. for 0.5 hour. Sodium triacetoxyborohydride (32 mg, 0.15 mmol, 2 eq)was added, and then the mixture was stirred at 25° C. for 12 hours. LCMSanalysis of the crude reaction mixture showed the reaction was complete.The pH of the reaction mixture was adjusted to between 6 and 7 withaddition of hydrochloric acid (0.5 mL) and was then concentrated. Theresidue was purified by semi-preparative reverse phase HPLC to affordN-(5-((4-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)ethyl)piperazin-1-yl)methyl)-1-((1s,4s)-4-(hydroxymethyl)cyclohexyl)-1H-benzo[d]imidazol-2-yl)-3-(trifluoromethyl)benzamide(33.8 mg, 0.03 mmol, 46% yield, 96% purity, formate) as a white solid.MS (ESI) m/z: 816.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ: 12.82 (s, 1H),11.11 (s, 1H), 8.50 (d, J=8.0 Hz, 1H), 8.45 (s, 1H), 8.21 (s, 1H), 7.90(d, J=8.0 Hz, 1H), 7.82 (d, J=8.4 Hz, 1H), 7.77-7.71 (m, 1H), 7.56-7.51(m, 2H), 7.45 (d, J=2.0 Hz, 1H), 7.35 (dd, J=2.0, 8.4 Hz, 1H), 7.19 (d,J=8.4 Hz, 1H), 5.11 (dd, J=5.2, 13.2 Hz, 1H), 4.79-4.66 (m, 1H), 4.28(t, J=5.6 Hz, 2H), 3.68 (d, J=7.6 Hz, 2H), 3.52 (s, 1H), 2.93-2.84 (m,1H), 2.73 (t, J=5.4 Hz, 2H), 2.64-2.56 (m, 2H), 2.55-2.51 (m, 8H),2.46-2.35 (m, 4H), 2.10-2.00 (m, 1H), 1.98-1.89 (m, 2H), 1.88-1.80 (m,1H), 1.74-1.56 (m, 4H).

Exemplary Synthesis of Exemplary Compound 2N-(5-((4-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)ethoxy)ethyl)piperazin-1-yl)methyl)-1-((1s,4s)-4-(hydroxymethyl)cyclohexyl)-1H-benzo[d]imidazol-2-yl)-3-(trifluoromethyl)benzamide

To a solution of2-[2-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]oxyethoxy]ethyl4-methylbenzenesulfonate, Intermediate 10 (50 mg, 0.096 mmol, 1.25 eq)andN-(1-((1s,4s)-4-(hydroxymethyl)cyclohexyl)-5-(piperazin-1-ylmethyl)-1H-benzo[d]imidazol-2-yl)-3-(trifluoromethyl)benzamide(Example 1 intermediate) (40 mg, 0.077 mmol, 1 eq) in acetonitrile (2mL) was added N,N-diisopropylethylamine (30 mg, 0.23 mmol, 3 eq) andpotassium iodide (1.29 mg, 0.007 mmol, 0.1 eq). The mixture was stirredat 90° C. for 12 hours. LCMS analysis indicated completion of thereaction. The reaction mixture was concentrated and the resultingresidue was purified by preparative HPLC to affordN-(5-((4-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)ethoxy)ethyl)piperazin-1-yl)methyl)-1-((1s,4s)-4-(hydroxymethyl)cyclohexyl)-1H-benzo[d]imidazol-2-yl)-3-(trifluoromethyl)benzamide(32.5 mg, 0.034 mmol, 44% yield, 96% purity, formate) as a white solid.MS (ESI) m/z: 860.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d6) δ: 12.82 (s, 1H),11.11 (s, 1H), 8.55-8 .38 (m, 2H), 8.21 (s, 1H), 7.90 (d, J=8.4 Hz, 1H),7.82 (d, J=8.4 Hz, 1H), 7.77-7.70 (m, 1H), 7.56-7.49 (m, 2H), 7.45 (d,J=2.0 Hz, 1H), 7.36 (dd, J=2.4, 8.4 Hz, 1H), 7.18 (d, J=8.4 Hz, 1H),5.11 (dd, J=5.2, 13.0 Hz, 1H), 4.72 (s, 1H), 4.58 (s, 1H), 4.30 (d,J=4.4 Hz, 2H), 3.76 (s, 2H), 3.68 (d, J=7.2 Hz, 3H), 3.57 (t, J=6.0 Hz,3H), 3.49 (s, 4H), 2.98-2.79 (m, 2H), 2.63-2.56 (m, 1H), 2.46-2.38 (m,6H), 2.10-1.99 (m, 2H), 1.94 (d, J=13.6 Hz, 2H), 1.85 (s, 2H), 1.72-1.56(m, 4H).

The following compounds may be prepared in an analogous fashion as theexemplary synthesis described for Exemplary Compound 2.

Exemplar Compound [M + H]⁺

860.68

904.72

948.75

846.4

n.d.

n.d.

Exemplary Synthesis of Exemplary Compound 9N-(5-((4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperazin-1-yl)methyl)-1-((1s,4s)-4-(hydroxymethyl)cyclohexyl)-1H-benzo[d]imidazol-2-yl)-3-(trifluoromethyl)benzamide

Step 1:

To a solution ofN-(1-((1s,4s)-4-(hydroxymethyl)cyclohexyl)-5-(piperazin-1-ylmethyl)-1H-benzo[d]imidazol-2-yl)-3-(trifluoromethyl)benzamide(Example 1 intermediate) (80 mg, 0.14 mmol, 1.00 eq, hydrochloric acid)in 1,2-dichloroethane (2 mL) was added tert-butyl4-formylpiperidine-1-carboxylate (34 mg, 0.16 mmol, 1.10 eq) sodiumcyanoborohydride (18 mg, 0.29 mmol, 2.00 eq) solution. The mixture wasstirred at 30° C. for 12 hours. The mixture was concentrated underreduced pressure and the resulting residue was purified by silica gelchromatography eluting with 10% methyl alcohol in dichloromethane. Theappropriate fractions were pooled and concentrated to obtain tert-butyl4-((4-((1-((1s,4s)-4-(hydroxymethyl)cyclohexyl)-2-(3-(trifluoromethyl)benzamido)-1H-benzo[d]imidazol-5-yl)methyl)piperazin-1-yl)methyl)piperidine-1-carboxylate(0.10 g, crude) as a colorless oil. MS (ESI) m/z: 713.2 [M+H]+.

Step 2:

To a solution of tert-butyl4-((4-((1-((1s,4s)-4-(hydroxymethyl)cyclohexyl)-2-(3-(trifluoromethyl)benzamido)-1H-benzo[d]imidazol-5-yl)methyl)piperazin-1-yl)methyl)piperidine-1-carboxylate(100 mg, 0.14 mmol, 1.00 eq) in ethyl acetate (1 mL) was added a 4 Msolution of hydrochloric acid in dioxane (1 mL, 28.5 eq). The mixturewas stirred at 25° C. for 0.5 hour. The mixture was concentrated underreduced pressure to affordN-(1-((1s,4s)-4-(hydroxymethyl)cyclohexyl)-5-((4-(piperidin-4-ylmethyl)piperazin-1-yl)methyl)-1H-benzo[d]imidazol-2-yl)-3-(trifluoromethyl)benzamide(85 mg, 0.12 mmol, 88% yield, 2 hydrochloride salt) as a white solidwhich was used in a subsequent transformation without furtherpurification. MS (ESI) m/z: 613.2 [M+H]⁺.

Step 3:

To a solution ofN-(1-((1s,4s)-4-(hydroxymethyl)cyclohexyl)-5-((4-(piperidin-4-ylmethyl)piperazin-1-yl)methyl)-1H-benzo[d]imidazol-2-yl)-3-(trifluoromethyl)benzamide(70 mg, 0.11 mmol, 1.00 eq, 2 hydrochloride salt) in dimethylsulfoxide(1 mL) was added diisopropylethylamine (44 mg, 0.34 mmol, 3.00 eq) and2-(2,6-dioxo-3-piperidyl)-5-fluoro-isoindoline-1,3-dione, Intermediate 2(32 mg, 0.11 mmol, 1.00 eq). The mixture was stirred at 120° C. for 1hour. LCMS analysis of the crude reaction mixture indicated completeconversion. The mixture was concentrated under reduced pressure toafford a residue which was purified by preparative HPLC. The appropriatefractions were concentrated to affordN-(5-((4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperazin-1-yl)methyl)-1-((1s,4s)-4-(hydroxymethyl)cyclohexyl)-1H-benzo[d]imidazol-2-yl)-3-(trifluoromethyl)benzamide(13.6 mg, 0.01 mmol, 12% yield, 98% purity, trifluoroacetic acid salt)as a yellow solid. MS (ESI) m/z: 869.4 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆)δ: 12.21-13.74 (m, 1H), 11.07 (s, 1H), 8.50 (d, J=7.6 Hz, 1H), 8.45 (s,1H), 7.91 (d, J=8.0 Hz, 1H), 7.75 (t, J=7.6 Hz, 1H), 7.58-7 .68 (m, 3H),7.33 (s, 2H), 7.25 (d, J=8.4 Hz, 1H), 5.06 (dd, J=5.2, 12.8 Hz, 1H),4.68-4.80 (m, 1H), 4.06 (d, J=12.4 Hz, 4H), 3.69 (d, J=7.2 Hz, 3H),2.81-3.02 (m, 8H), 2.58-2.69 (m, 2H), 2.33 (br s, 1H), 1.91-2.08 (m,5H), 1.75-1.90 (m, 4H), 1.58-1.74 (m, 5H), 1.14-1.28 (m, 3H), 1.05 (t,J=7.2 Hz, 2H).

Exemplary Synthesis of Exemplary Compound 10N-(5-((4-((1-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)ethyl)piperidin-4-yl)methyl)piperazin-1-yl)methyl)-1-((1s,4s)-4-(hydroxymethyl)cyclohexyl)-1H-benzo[d]imidazol-2-yl)-3-(trifluoromethyl)benzamide

To a solution ofN-(1-((1s,4s)-4-(hydroxymethyl)cyclohexyl)-5-((4-(piperidin-4-ylmethyl)piperazin-1-yl)methyl)-1H-benzo[d]imidazol-2-yl)-3-(trifluoromethyl)benzamide(Example 9 intermediate) (50 mg, 0.08 mmol, 1.00 eq, 2 hydrochloridesalt) in methyl alcohol (2 mL) was added2-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]oxyacetaldehyde,Intermediate 8 (29 mg, 0.09 mmol, 1.15 eq) and sodium cyanoborohydride(7 mg, 0.11 mmol, 1.27 eq). The mixture was stirred at 25° C. for 15hours after which the reaction mixture was concentrated under reducedpressure. The residue was purified by preparative HPLC to affordN-(5-((4-((1-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)ethyl)piperidin-4-yl)methyl)piperazin-1-yl)methyl)-1-((1s,4s)-4-(hydroxymethyl)cyclohexyl)-1H-benzo[d]imidazol-2-yl)-3-(trifluoromethyl)benzamide(14.8 mg, 0.01 mmol, 17% yield, 99% purity, trifluoroacetic acid) as awhite solid. MS (ESI) m/z: 913.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ:13.30-12.54 (m, 1H), 11.39-11.03 (m, 1H), 10.27-9.80 (m, 1H), 8.69-8.30(m, 2H), 7.99-7.85 (m, 2H), 7.76 (t, J=8.0 Hz, 1H), 7.72-7.59 (m, 2H),7.54 (d, J=2.0 Hz, 1H), 7.45-7.28 (m, 2H), 5.14 (dd, J=5.2, 12.8, Hz,1H), 4.81-4.69 (m, 1H), 4.57 (s, 2H), 4.29-4.08 (m, 3H), 3.70-3.56 (m,10H), 3.09-2.81 (m, 7H), 2.65-2.54 (m, 6H), 2.10-2.03 (m, 1H), 2.00-1.82(m, 6H), 1.73-1.60 (m, 4H), 1.41 (d, J=11.6 Hz, 2H).

A compound of formula I may be reacted with a reagent II (commerciallyavailable or readily prepared using standard reaction techniques knownto one skilled in the art) where Y is an appropriate leaving group (e.g.OMs, OTs, Cl, Br etc.) or an aldehyde, under suitable alkylation orreductive amination conditions to produce a compound of formula III,wherein L represents an optional linker or portion of a linker, and X isa protecting group. When Y is a leaving group, suitable reactionconditions are those for an alkylation reaction, e.g.diisopropylethylamine, potassium iodide, DMSO or acetonitrile, 80° C.When Y is an aldehyde, suitable reaction conditions are those for areductive amination reaction, e.g. sodium cyanoborohydride, methanol,dichloromethane, acetic acid, room temperature. After deprotection ofthe ester, compounds of formula IV may react with a compound of formulaV through amide coupling conditions known to one skilled in the art,e.g. HATU or HOBt, EDCI, TEA, in DMF to provide compounds of formula VI.

Exemplary Synthesis of Exemplary Compound 11(2S,4R)-4-hydroxy-1-((S)-2-(2-(2-(4-((1-((1SR,4SR)-4-(hydroxymethyl)cyclohexyl)-2-(3-(trifluoromethyl)benzamido)-1H-benzo[d]imidazol-5-yl)methyl)piperazin-1-yl)ethoxy)acetamido)-3,3-dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

Step 1:

To a solution ofN-(1-((1s,4s)-4-(hydroxymethyl)cyclohexyl)-5-(piperazin-1-ylmethyl)-1H-benzo[d]imidazol-2-yl)-3-(trifluoromethyl)benzamide(Example 1 intermediate) (50 mg, 97 μmol, 1.0 eq) in acetonitrile (2 mL)was added ethyl 2-(2-chloroethoxy)acetate (32.3 mg, 194 μmol, 2.0 eq)and diisopropylethylamine (25.1 mg, 194 μmol, 33.8 μL, 2.00 eq). Themixture was stirred for 10 hours at 80° C. LCMS analysis of the crudereaction mixture showed that the reaction was complete. The mixture wasfiltered. The filtrate was concentrated under reduced pressure and theresulting residue was purified by preparative TLC(dichloromethane:methanol=10:1) to afford ethyl2-(2-(4-((1-((1s,4s)-4-(hydroxymethyl)cyclohexyl)-2-(3-(trifluoromethyl)benzamido)-1H-benzo[d]imidazol-5-yl)methyl)piperazin-1-yl)ethoxy)acetate(55.0 mg, 85.2 μmol, 87% yield) as a brown oil, which was used in asubsequent reaction without further purification. MS (ESI) m/z: 646.2[M+H]⁺.

Step 2:

To a solution of ethyl2-(2-(4-((1-((1s,4s)-4-(hydroxymethyl)cyclohexyl)-2-(3-(trifluoromethyl)benzamido)-1H-benzo[d]imidazol-5-yl)methyl)piperazin-1-yl)ethoxy)acetate(55 mg, 85.2 μmol, 1.00 eq) in methanol (2 mL) and water (1 mL) wasadded sodium hydroxide (6.81 mg, 170.3 μmol, 2.00 eq). The mixture wasstirred for 0.5 hour at 30° C. LCMS analysis of the crude reactionmixture showed that the reaction was complete. The mixture wasconcentrated under reduced pressure and the resulting residue wasdiluted with water (1 mL) and the pH was adjusted to 3 with a 1 Maqueous solution of hydrochloride. The mixture was concentrated underreduced pressure to afford a residue which was purified byre-crystallization from 10 mL of dichloromethane to provide2-(2-(4-((1-((1s,4s)-4-(hydroxymethyl)cyclohexyl)-2-(3-(trifluoromethyl)benzamido)-1H-benzo[d]imidazol-5-yl)methyl)piperazin-1-yl)ethoxy)aceticacid (50.0 mg, 80.9 μmol, 95% yield) as a yellow solid, which was usedas is in a subsequent reaction. MS (ESI) m/z: 618.2 [M+H]⁺.

Step 3:

To a solution of2-(2-(4-((1-((1s,4s)-4-(hydroxymethyl)cyclohexyl)-2-(3-(trifluoromethyl)benzamido)-1H-benzo[d]imidazol-5-yl)methyl)piperazin-1-yl)ethoxy)aceticacid (50.0 mg, 80.9 μmol, 1.00 eq) in N,N-dimethylformamide (1 mL) wasadded triethylamine (24.57 mg, 242.8 μmol, 33.8 μL, 3.00 eq),hydroxybenzotriazole (16.41 mg, 121.43 μmol, 1.50 eq),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (23.28 mg,121.43 μmol, 1.50 eq) and(2S,4R)-1-[(2S)-2-amino-3,3-dimethyl-butanoyl]-4-hydroxy-N—[[4-(4-methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide (41.83mg, 97.14 μmol, 1.20 eq). Then the mixture was stirred for 10 hours at30° C. LCMS analysis of the crude reaction mixture showed that thereaction was complete. The mixture was filtered and the filtrate waspurified by preparative HPLC to give(2S,4R)-4-hydroxy-1-((S)-2-(2-(2-(4-((1-((1SR,4SR)-4-(hydroxymethyl)cyclohexyl)-2-(3-(trifluoromethyl)benzamido)-1H-benzo[d]imidazol-5-yl)methyl)piperazin-1-yl)ethoxy)acetamido)-3,3-dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide(12.7 mg, 10.8 μmol, 13% yield, 97% purity, trifluoroacetic salt) as ayellow solid. MS(ESI) m/z: 1030.5 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ:12.94 (s, 1H), 8.96-9.00 (m, 1H), 8.60 (t, J=6.0 Hz, 1H), 8.50 (d, J=8.0Hz, 1H), 8.45 (s, 1H), 7.92 (d, J=7.6 Hz, 1H), 7.85 (br d, J=10.0 Hz,1H), 7.76 (t, J=7.6 Hz, 1H), 7.65 (d, J=8.4 Hz, 1H), 7.60 (s, 1H),7.35-7.46 (m, 5H), 7.31 (br d, J=8.8 Hz, 1H), 4.72 (br d, J=10.4 Hz,2H), 4.58 (d, J=9.6 Hz, 1H), 4.33-4.47 (m, 4H), 4.19-4.31 (m, 2H),3.96-4.15 (m, 7H), 3.71-3.79 (m, 7H), 2.96-3.38 (m, 2H), 2.43 (s, 4H),2.02-2.12 (m, 1H), 1.81-2.01 (m, 5H), 1.55-1.80 (m, 5H), 0.87-1.01 (m,11H).

The following compounds may be prepared in an analogous fashion as theexemplary synthesis described for Exemplary Compound 11.

Exemplary Compound [M + H]⁺

1074.5

1118.6

1162.6

Exemplary Synthesis of Exemplary Compound 25N-(3-(4-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)ethoxy)ethoxy)ethyl)piperazin-1-yl)-1-(5-methylpyridin-2-yl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Step 1:

To a solution of ethyl 2-cyanoacetate (100 g, 884.06 mmol, 94.3 mL, 1eq) and methanedithione (67.31 g, 884.06 mmol, 53.4 mL, 1 eq) in ethanol(1100 mL) was added sodium hydroxide (70.72 g, 1.77 mol, 2 eq) in water(72 mL) at 0° C. dropwise. The mixture was warmed to 10° C. and stirredat 10° C. for 10 minutes. Then the mixture was cooled to 5° C. Themixture was filtered. The filter cake was triturated with petroleumether and ethanol (300 mL, V:V=5:1 to afford[(Z)-2-cyano-3-ethoxy-3-oxo-1-sodiosulfanuidyl-prop-1-enyl]sulfanylsodium(200 g, 857.56 mmol, 97% yield) as a yellow solid.

Step 2:

To a solution of sodium hydroxide (59.75 g, 1.49 mol, 1.74 eq) in water(420 mL) was added[(Z)-2-cyano-3-ethoxy-3-oxo-1-sodiosulfanuidyl-prop-1-enyl]sulfanylsodium(200 g, 857.56 mmol, 1 eq). The mixture was stirred at 40° C. for 5hours. The mixture was cooled to 15° C. and then the mixture was dilutedwith ethanol (740 mL). The aqueous layer was separated and diluted withwater to a total volume of (900 mL). The solution was cooled to 5° C.,and dimethyl sulfate (184.96 g, 1.47 mol, 139.07 mL, 1.71 eq) was addedat a rate such that the internal temperature was maintained below 15° C.Once the addition was complete, the temperature was maintained between15 and 30° C. for 40 minutes. The solution was cooled to 15° C. and themixture was filtered. The pH of the filtrate was adjusted 2 with theaddition of a 4 M aqueous solution of hydrochloric acid. The mixture wasstirred at 20° C. for 0.5 hour, the solid formed was filtered. Thefilter cake was dissolved in ethyl acetate (500 mL), dried withanhydrous sodium sulfate, filtered and concentrated under vacuum toprovide 2-cyano-3,3-bis (methylsulfanyl)prop-2-enoic acid (80 g, 422.7mmol, 49% yield) as a yellow solid.

Step 3:

To a solution of 2-cyano-3,3-bis(methylsulfanyl)prop-2-enoic acid (80 g,422.7 mmol, 1 eq) in methanol (800 mL) was added tert-butylpiperazine-1-carboxylate (157.46 g, 845.42 mmol, 2 eq) and triethylamine(42.77 g, 422.71 mmol, 58.84 mL, 1 eq) at 0° C. The mixture was stirredat 0° C. for 3 hours. The mixture was concentrated under reducedpressure and the resulting residue was used in the next step withoutfurther purification. Compound tert-butyl4-[(Z)-2-cyano-1-methylsulfanyl-vinyl]piperazine-1-carboxylate (120 g,crude) was obtained as a yellow oil.

Step 4:

To a solution of tert-butyl4-[(Z)-2-cyano-1-methylsulfanyl-vinyl]piperazine-1-carboxylate (120 g,423.45 mmol, 1 eq) in ethanol (960 mL) was added hydrazine hydrate(86.52 g, 1.69 mol, 84 mL, 4 eq). The mixture was stirred at 80° C. for12 hours. Thin layer chromatography (dichloromethane:methanol=10:1)analysis confirmed the reaction was complete. The mixture wasconcentrated under vacuum. The residue was purified by silica gelchromatography to afford tert-butyl4-(5-amino-1H-pyrazol-3-yl)piperazine-1-carboxylate (35 g, 121.76 mmol,28% yield, 93% purity) as a yellow oil. MS (ESI) m/z: 268.2 [M+H]⁺.

Step 5:

To a solution of tert-butyl4-(5-amino-1H-pyrazol-3-yl)piperazine-1-carboxylate (649 mg, 1.87 mmol,1 eq) in dimethylsulfoxide (10 mL) was added 2-bromo-5-methyl-pyridine(337 mg, 1.96 mmol, 1.05 eq), cuprous iodide (35 mg, 0.19 mmol, 0.1 eq),cesium carbonate (1.22 g, 3.74 mmol, 2 eq) and L-proline (21 mg, 0.19mmol, 0.1 eq). The mixture was stirred at 130° C. for 12 hours undernitrogen atmosphere. LCMS analysis of an aliquot showed the reaction wascomplete. The mixture was diluted with water (10 mL) and extracted withethyl acetate (10 mL×3). The combined organic layers were washed withbrine (30 mL×3), dried with anhydrous sodium sulfate, filtered andconcentrated under reduced pressure. The resulting residue was purifiedby column chromatography (petroleum ether:ethyl acetate=20:1) to givetert-butyl4-[5-amino-1-(5-methyl-2-pyridyl)pyrazol-3-yl]piperazine-1-carboxylate(150 mg, 0.42 mmol, 22% yield) as a white solid. MS (ESI) m/z:359.2[M+H]⁺. ¹H NMR (400 MHz, DMSO-d6) δ: 8.13 (s, 1H), 7.67 (dd, J=2.0,8.8 Hz, 1H), 7.60-7.54 (m, 1H), 6.75 (s, 2H), 5.01 (s, 1H), 3.44-3.36(m, 4H), 3.15-3.05 (m, 4H), 2.26 (s, 3H), 1.41 (s, 9H).

Step 6:

To a solution of tert-butyl4-[5-amino-1-(5-methyl-2-pyridyl)pyrazol-3-yl]piperazine-1-carboxylate(250 mg, 0.70 mmol, 1 eq) and pyrazolo[1,5-a]pyrimidine-3-carbonylchloride, Intermediate 4 (200 mg, 1.10 mmol, 1.58 eq) in dichloromethane(8 mL) was added triethylamine (705 mg, 6.97 mmol, 10 eq). The mixturewas stirred at 20° C. for 1 hour. LCMS analysis of an aliquot indicatedcomplete conversion. The mixture was concentrated under reduced pressureand the resulting residue was purified by preparative reverse phase HPLCto give tert-butyl4-[1-(5-methyl-2-pyridyl)-5-(pyrazolo[1,5-a]pyrimidine-3-carbonylamino)pyrazol-3-yl]piperazine-1-carboxylate(60 mg, 0.12 mmol, 17% yield) as a light yellow oil. ¹H NMR (400 MHz,DMSO-d₆) δ: 13.27 (s, 1H), 9.39 (dd, J=1.6, 7.2 Hz, 1H), 9.15 (dd,J=1.6, 4.0 Hz, 1H), 8.73 (s, 1H), 8.46 (s, 1H), 7.81 (dd, J=2.4, 8.4 Hz,1H), 7.69 (d, J=8.8 Hz, 1H), 7.38 (dd, J=4.0, 7.2 Hz, 1H), 6.67 (s, 1H),3.51-3.42 (m, 4H), 3.28-3.20 (m, 4H), 2.38 (s, 3H), 1.43 (s, 9H).

Step 7:

To a solution of tert-butyl4-[1-(5-methyl-2-pyridyl)-5-(pyrazolo[1,5-a]pyrimidine-3-carbonylamino)pyrazol-3-yl]piperazine-1-carboxylate(60 mg, 0.12 mmol, 1 eq) in dichloromethane (1 mL) was addedhydrochloric acid in dioxane (4.0 M, 5 mL). The mixture was stirred at20° C. for 0.5 hour. Thin layer chromatography (petroleum ether: ethylacetate=1:1) showed the reaction to be complete. The mixture wasconcentrated under reduced pressure and the obtained crude product wasused in the next step without further purification. CompoundN-[2-(5-methyl-2-pyridyl)-5-piperazin-1-yl-pyrazol-3-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(50 mg, 0.11 mmol, 95% yield, hydrochloride) was obtained as a yellowsolid.

Step 8:

To a solution ofN-[2-(5-methyl-2-pyridyl)-5-piperazin-1-yl-pyrazol-3-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide(47 mg, 0.11 mmol, 1.2 eq, hydrochloride) and2-[2-[2-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]oxyethoxy]ethoxy]ethyl4-methylbenzenesulfonate, prepared in an analogous fashion toIntermediate 10, (50 mg, 0.09 mmol, 1 eq) in acetonitrile (2 mL) wasadded N,N-diisopropylethylamine (34 mg, 0.27 mmol, 3 eq) and potassiumiodide (14 mg, 0.09 mmol, 1 eq). The mixture was stirred at 80° C. for12 hours. LCMS analysis showed the reaction to be complete. The mixturewas adjusted to pH=7 by addition of an aqueous 1 M solution ofhydrochloric acid. The mixture was filtered and the residue was purifiedby preparative reverse phase HPLC to giveN-(3-(4-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)ethoxy)ethoxy)ethyl)piperazin-1-yl)-1-(5-methylpyridin-2-yl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(19.3 mg, 0.02 mmol, 25% yield, 98% purity, formate) as a yellow solid.MS (ESI) m/z: 792.3 [M+H]⁺. ¹H NMR: (400 MHz, DMSO-d₆) δ: 13.27 (s, 1H),11.11 (s, 1H), 9.38 (dd, J=1.6, 7.2 Hz, 1H), 9.14 (dd, J=1.6, 4.4 Hz,1H), 8.73 (s, 1H), 8.44 (s, 1H), 8.23 (s, 1H), 7.83 (d, J=8.4 Hz, 1H),7.79 (dd, J=2.4, 8.8 Hz, 1H), 7.67 (d, J=8.4 Hz, 1H), 7.46 (d, J=2.4 Hz,1H), 7.40-7.35 (m, 2H), 6.62 (s, 1H), 5.11 (dd, J=5.2, 12.8 Hz, 1H),4.41-4.27 (m, 2H), 3.83-3.78 (m, 2H), 3.63-3.59 (m, 3H), 3.58-3.53 (m,6H), 3.24-3.19 (m, 3H), 2.93-2.80 (m, 2H), 2.62-2.56 (m, 2H), 2.55-2.53(m, 3H), 2.37 (s, 3H), 2.07-2.00 (m, 1H).

The following compounds may be prepared in an analogous fashion as theexemplary synthesis described Exemplary Compound 25.

Exemplary Compound [M + H]⁺

836.66

A compound of formula I may be reacted with a reagent II (commerciallyavailable or readily prepared using standard reaction techniques knownto one skilled in the art) under alkylation or reductive alkylationconditions to produce a compound of formula III, wherein L represents anoptional linker or portion of a linker, Y is an appropriate leavinggroup (e.g. OMs, OTs, Cl, etc.) or an aldehyde, and X is a protectinggroup. When Y is a leaving group, suitable reaction conditions are thosefor an alkylation reaction, e.g. diisopropylethylamine, potassiumiodide, DMSO or acetonitrile, 80° C. When Y is an aldehyde, suitablereaction conditions are those for a reductive amination reaction, e.g.sodium cyanoborohydride, methanol, dichloromethane, acetic acid, roomtemperature. Compounds of formula III may be deprotected to reveal acarboxylic acid as in compounds of formula IV. Compounds of formula IVcan then be reacted with a compound of formula V using suitable amidecoupling conditions, e.g., HOBT or HATU, EDCI, TEA in DMF, to affordcompounds of formula VI.

Exemplary Synthesis of Exemplary Compound 27N-(3-(4-((S)-13-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidine-1-carbonyl)-14,14-dimethyl-11-oxo-3,6,9-trioxa-12-azapentadecyl)piperazin-1-yl)-1-(5-methylpyridin-2-yl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Step 1:

To a solution of tert-butyl2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]acetate (200 mg, 0.75 mmol, 1eq), 4-dimethylaminopyridine (9.24 mg, 0.075 mmol, 0.1 eq) andtriethylamine (229 mg, 2.27 mmol, 3 eq) in dichloromethane (3 mL) wasadded tosyl chloride (216 mg, 1.14 mmol, 1.5 eq). The reaction mixturewas stirred at 30° C. for 12 hours. LCMS analysis of an aliquot showedformation of the desired compound. The reaction mixture was diluted withwater (50 mL) and extracted with ethyl acetate (30 mL×3). The combinedorganic layers were washed with brine (50 mL×3), dried over anhydroussodium sulfate, filtered and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (petroleumether/ethyl acetate=100/1 to 3:1). The appropriate fractions were pooledand concentrated to afford tert-butyl2-[2-[2-[2-(p-tolylsulfonyloxy)ethoxy]ethoxy]ethoxy]acetate (200 mg,0.47 mmol, 63% yield) was obtained as a colorless oil. MS (ESI) m/z:363.1 [M−55]+.

Step 2:

To a solution ofN-[2-(5-methyl-2-pyridyl)-5-piperazin-1-yl-pyrazol-3-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (100 mg, 0.22 mmol, 1 eq, Hydrochloride),N,N-diisopropylethylamine (88 mg, 0.68 mmol, 3 eq) and tert-butyl2-[2-[2-[2-(p-tolylsulfonyloxy)ethoxy]ethoxy]ethoxy]acetate (95 mg, 0.22mmol, 1 eq) in acetonitrile (5 mL) was stirred at 70° C. for 12 hours.LCMS analysis of an aliquot showed formation of the desired compound.The reaction mixture was diluted with water (30 mL) and extracted withethyl acetate (30 mL×3). The combined organic layers were washed withbrine (30 mL×3), dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure. The residue was purified bypreparative TLC (dichloromethane:methanol=10:1) to provide tert-butyl2-[2-[2-[2-[4-[1-(5-methyl-2-pyridyl)-5-(pyrazolo[1,5-a]pyrimidine-3-carbonylamino)pyrazol-3-yl]piperazin-1-yl]ethoxy]ethoxy]ethoxy]acetate(80 mg, 0.12 mmol, 54% yield) as a yellow oil. MS (ESI) m/z: 650.3[M+H]⁺.

Step 3:

To a solution of tert-butyl2-[2-[2-[2-[4-[1-(5-methyl-2-pyridyl)-5-(pyrazolo[1,5-a]pyrimidine-3-carbonylamino)pyrazol-3-yl]piperazin-1-yl]ethoxy]ethoxy]ethoxy]acetate(80 mg, 0.12 mmol, 1 eq) in dichloromethane (1 mL) was addedtrifluoroacetic acid (1.54 g, 13.51 mmol, 1 mL, 109 eq). The reactionmixture was stirred at 30° C. for 0.5 hour. LCMS analysis showedformation of the desired compound. The reaction mixture was concentratedunder reduced pressure providing2-[2-[2-[2-[4-[1-(5-methyl-2-pyridyl)-5-(pyrazolo[1,5-a]pyrimidine-3-carbonylamino)pyrazol-3-yl]piperazin-1-yl]ethoxy]ethoxy]ethoxy]aceticacid (80 mg, 0.11 mmol, 91% yield, trifluoroacetic acid) as a yellow oilwhich was used directly in the next transformation. MS (ESI) m/z: 594.2[M+H]⁺.

Step 4:

To a solution of2-[2-[2-[2-[4-[1-(5-methyl-2-pyridyl)-5-(pyrazolo[1,5-a]pyrimidine-3-carbonylamino)pyrazol-3-yl]piperazin-1-yl]ethoxy]ethoxy]ethoxy]aceticacid (80 mg, 0.11 mmol, 1 eq, trifluoroacetic acid),(2S,4R)-1-(2-amino-3,3-dimethyl-butanoyl)-4-hydroxy-N-[[4-(4-methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide(63 mg, 0.13 mmol, 1.2 eq, hydrochloride), hydroxybenzotriazole (18 mg,0.13 mmol, 1.2 eq) and N,N-diisopropylethylamine (17 mg, 0.13 mmol, 1.2eq) in N,N-dimethylformamide (5 mL) was stirred at 30° C. for 0.5 hour.Then 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (26 mg,0.13 mmol, 1.2 eq) was added. The reaction mixture was stirred at 30° C.for 12 hours. LCMS analysis indicated formation of the desired compound.The reaction mixture was filtered and concentrated under reducedpressure. The residue was purified by preparative HPLC to yieldN-(3-(4-((S)-13-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidine-1-carbonyl)-14,14-dimethyl-11-oxo-3,6,9-trioxa-12-azapentadecyl)piperazin-1-yl)-1-(5-methylpyridin-2-yl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(44.3 mg, 0.04 mmol, 36% yield, 99% purity, formate) as a yellow solid.MS (ESI) m/z: 594.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ:13.26 (s, 1H),9.43-9.33 (m, 1H), 9.16-9.09 (m, 1H), 8.98 (s, 1H), 8.75-8.68 (m, 1H),8.62 (t, J=6.1 Hz, 1H), 8.43 (s, 1H), 8.19 (s, 1H), 7.81-7.74 (m, 1H),7.67 (d, J=8.4 Hz, 1H), 7.48-7.33 (m, 6H), 6.63 (s, 1H), 4.58 (d, J=9.5Hz, 1H), 4.50-4.34 (m, 3H), 4.29-4.21 (m, 1H), 3.99 (s, 2H), 3.69-3.55(m, 21H), 2.44 (s, 3H), 2.36 (s, 3H), 2.11-2.02 (m, 1H), 1.95-1.86 (m,1H), 1.04-0.90 (m, 9H).

The following compounds may be prepared in an analogous fashion as theexemplary synthesis described for Exemplary Compound 27.

Exemplary Compound [M + H]⁺

1050.25

A compound of formula I may be reacted with a reagent II (commerciallyavailable or readily prepared using standard reaction techniques knownto one skilled in the art) where Z is an appropriate leaving group (e.g.OMs, OTs, Cl, Br, etc.) using O-alkylation conditions to produce acompound of formula III, wherein L represents an optional linker orportion of a linker, X is CH₂ or C═N. Compounds of formula III may reactwith a compound of formula IV through N-alkylation where Y is anappropriate leaving group (e.g. OMs, OTs, Cl, Br, etc.) or throughreductive amination where Y is an aldehyde to produce compound offormula V. When Y is a leaving group, suitable reaction conditions arethose for an alkylation reaction, e.g. diisopropylethylamine, potassiumiodide, DMSO or acetonitrile, 80° C. When Y is an aldehyde, suitablereaction conditions are those for a reductive amination reaction, e.g.sodium cyanoborohydride, methanol, dichloromethane, acetic acid, roomtemperature.

Exemplary Synthesis of Exemplary Compound 294-(((1r,4r)-4-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)ethyl)piperazin-1-yl)cyclohexyl)amino)quinazoline-6-carbonitrile

Step 1:

6-bromoquinazolin-4-ol (2 g, 8.89 mmol, 1 eq), zinc cyanide (1.57 g,13.33 mmol, 1.5 eq) and tetrakis[triphenylphosophine] palladium(O) (1.03g, 0.88 mmol, 0.1 eq) were charged to a microwave tube inN,N-dimethylformamide (10 mL) under nitrogen atmosphere. The sealed tubewas heated at 120° C. for 120 minutes under microwave irradiation. Themixture was filtered and the filtrate was diluted with ethyl acetate(1000 mL). The mixture was washed with brine (500 mL), dried withanhydrous sodium sulfate, filtered and concentrated under vacuum. Thecrude product was purified by silica gel column chromatography(petroleum ether: ethyl acetate=10:1 to dichloromethane:methanol=10:1)to give 4-hydroxyquinazoline-6-carbonitrile (1.2 g, 7.01 mmol, 39%yield) as a white solid.

Step 2:

To a solution of 4-hydroxyquinazoline-6-carbonitrile (1 g, 5.84 mmol, 1eq) in phosphorus oxychloride (107.61 mmol, 10 mL, 18.42 eq) was addedN,N-diethylaniline (2.18 g, 14.61 mmol, 2.34 mL, 2.5 eq). The mixturewas stirred at 110° C. for 3 hours under nitrogen atmosphere. Themixture was concentrated under reduced pressure and the resultingresidue was poured into (100 mL) ice water and stirred for 5 minutes.The mixture was filtered and to the filter cake was added 20 mLmethylbenzene. The volatiles were removed under vacuum and4-chloroquinazoline-6-carbonitrile (600 mg, 3.16 mmol, 54% yield) wasthus obtained as a blue solid.

Step 3:

To a solution of benzyl 4-(4-aminocyclohexyl)piperazine-1-carboxylate,Intermediate 5 (10.83 g, 30.59 mmol, 1 eq, hydrochloride) indimethylacetamide (150 mL) was added N,N-diisopropylethylamine (31.63 g,244 mmol, 8 eq). The mixture was stirred at 25° C. for 0.5 hour. Then4-chloroquinazoline-6-carbonitrile (5.8 g, 30.59 mmol, 1 eq) was addedto the mixture. The mixture was stirred at 25° C. for 4 hours. LCMSanalysis indicated the reaction was complete. The mixture was dilutedwith water (300 mL) and extracted with ethyl acetate (200 mL×5). Thecombined organic layers were washed with brine (500 mL×3), dried withanhydrous sodium sulfate, filtered and concentrated in vacuum. Theresidue was purified by preparative reverse phase HPLC to give benzyl4-((1r,4r)-4-((6-cyanoquinazolin-4-yl)amino)cyclohexyl)piperazine-1-carboxylate(3.85 g, 8.18 mmol, 27% yield) as a light yellow solid. MS (ESI) m/z:471.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ: 8.71 (s, 1H), 8.09 (s, 1H),7.93-7 .85 (m, 2H), 7.41-7.30 (m, 5H), 5.15 (s, 2H), 4.29-4.17 (m, 1H),3.60-3.46 (m, 4H), 2.57 (s, 4H), 2.48-2.37 (m, 1H), 2.30 (d, J=9.6 Hz,2H), 2.00 (d, J=14.8 Hz, 2H), 1.58-1.56 (m, 1H), 1.55-1.46 (m, 2H),1.43-1.31 (m, 2H). The cis isomer, benzyl4-((1s,4s)-4-((6-cyanoquinazolin-4-yl)amino)cyclohexyl)piperazine-1-carboxylate(6.9 g, 14.66 mmol, 48% yield), was also obtained as a light yellowsolid.

Step 4:

To a solution of benzyl4-((1r,4r)-4-((6-cyanoquinazolin-4-yl)amino)cyclohexyl)piperazine-1-carboxylate(1.2 g, 2.55 mmol, 1 eq) in dichloromethane (120 mL) was addedtriethylamine (916 mg, 9.05 mmol, 3.55 eq) and palladium dichloride (452mg, 2.55 mmol, 1 eq) at 0° C. under nitrogen. Triethylsilane (3.85 g,33.15 mmol, 13 eq) was added and the mixture was stirred at 25° C. for 2hours. To the mixture was then added trifluoroacetic acid (5.82 g, 51.00mmol, 20 eq) and the reaction was allowed to stir at 25° C. for 1 hour.LCMS showed the reaction was complete. The reaction was adjusted to pHbetween 8 and 9 with the addition of a saturated aqueous solution ofsodium bicarbonate. The mixture was concentrated under reduced pressureand the resulting residue was triturated with dichloromethane:methanol(V/V=10:1, 220 mL) and stirred for 10 min. The mixture was filtered, andthe filtrate was concentrated to give the crude product. The residue waspurified by preparative reverse phase HPLC to give4-(((1r,4r)-4-(piperazin-1-yl)cyclohexyl)amino)quinazoline-6-carbonitrile(500 mg, 1.49 mmol, 58% yield) as a white solid. MS (ESI) m/z: 337.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ: 8.95 (d, J=1.6 Hz, 1H), 8.56 (s,1H), 8.27 (d, J=7.6 Hz, 1H), 8.06 (dd, J=1.6, 8.8 Hz, 1H), 7.76 (d,J=8.8 Hz, 1H), 4.12 (td, J=3.6, 7.6 Hz, 1H), 2.68 (t, J=4.4 Hz, 4H),2.44 (d, J=4.4 Hz, 4H), 2.25 (t, J=11.2 Hz, 1H), 2.04 (d, J=11.2 Hz,2H), 1.86 (d, J=11.2 Hz, 2H), 1.50-1.30 (m, 4H).

Step 5:

To a solution of4-(((1r,4r)-4-(piperazin-1-yl)cyclohexyl)amino)quinazoline-6-carbonitrile(40 mg, 0.11 mmol, 1 eq) in 2-dichloroethane (4 mL) was addedtriethylamine (36 mg, 0.35 mmol, 3 eq) and2-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]oxyacetaldehyde,Intermediate 8 (37 mg, 0.11 mmol, 1 eq). The mixture was stirred at 25°C. for 0.5 hour, after which, sodium triacetoxyborohydride (50 mg, 0.23mmol, 2 eq) was added, the mixture was stirred at 25° C. for 1.5 hours.LCMS showed the reaction was complete. The reaction mixture wasconcentrated and the resulting residue was purified by semi-preparativereverse phase HPLC to give4-(((1r,4r)-4-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)ethyl)piperazin-1-yl)cyclohexyl)amino)quinazoline-6-carbonitrile(36.5 mg, 0.05 mmol, 44% yield, 98% purity, formate) as a white solid.MS (ESI) m/z: 637.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ: 11.10 (s, 1H),8.94 (d, J=1.6 Hz, 1H), 8.55 (s, 1H), 8.27 (d, J=7.2 Hz, 1H), 8.21 (s,1H), 8.05 (dd, J=2.0, 8.4 Hz, 1H), 7.83 (d, J=8.4 Hz, 1H), 7.76 (d,J=8.4 Hz, 1H), 7.46 (d, J=2.0 Hz, 1H), 7.37 (dd, J=2.4, 8.4 Hz, 1H),5.12 (dd, J=5.2, 12.8 Hz, 1H), 4.29 (t, J=5.6 Hz, 2H), 4.12 (d, J=7.2Hz, 1H), 2.93-2.84 (m, 1H), 2.72 (t, J=5.6 Hz, 2H), 2.61 (d, J=2.8 Hz,2H), 2.55-2.52 (m, 8H), 2.31-2.25 (m, 1H), 2.09-2.00 (m, 3H), 1.92-1.83(m, 2H), 1.49-1.32 (m, 4H).

The following compounds may be prepared in an analogous fashion as theexemplary synthesis described for Exemplary Compound 29.

Exemplary Compound [M + H]⁺

681.59

725.63

769.67

813.7

A compound of formula I may be reacted with a reagent II (commerciallyavailable or readily prepared using standard reaction techniques knownto one skilled in the art) under conjugate addition conditions, e.g. NaHin THF at room temperature, to produce a compound of formula III,wherein L represents an optional linker or portion of a linker and X isa protecting group. Compounds of formula III may be converted to acompound of formula IV through ether deprotection, e.g. using Pd/C, H₂,in MeOH or THF, room temperature, followed by N-Boc deprotection, e.g.with TFA or HCl in dioxane. A compound of formula IV may react with4-chloroquinazoline-6-carbonitrile via suitable nucleophilic aromaticsubstitution reaction conditions e.g., using a suitable base such asDIEA in DMF, to provide compounds of formula V whose relativestereochemical cis and trans regioisomers may be separated if desired.The alcohol in the compound of formula V may be converted to anappropriate leaving group Y (OTs, OMs, Cl, Br, etc) using standardreaction conditions known to one skilled in the art to provide acompound of formula VI. A compound of formula VI can react via anO-alkylation reaction with2-(2,6-dioxo-3-piperidyl)-5-hydroxy-isoindoline-1,3-dione to affordcompounds of formula VII using a suitable base and solvent, e.g.potassium carbonate in DMF at 60° C.

Exemplary Synthesis of Exemplary Compound 344-(((1r,4r)-4-(4-((2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)ethoxy)ethyl)sulfonyl)piperazin-1-yl)cyclohexyl)amino)quinazoline-6-carbonitrile

Step 1:

To a solution of 2-benzyloxyethanol (814 mg, 5.35 mmol, 2 eq) intetrahydrofuran (20 mL) was added sodium hydride (214 mg, 5.35 mmol, 60%purity, 2 eq) at 0° C. The mixture was stirred at 0° C. for 0.5 hour.Then tert-butylN-[4-(4-vinylsulfonylpiperazin-1-yl)cyclohexyl]carbamate, Intermediate 6(1 g, 2.68 mmol, 1 eq) in tetrahydrofuran (20 mL) was added dropwise tothe mixture at 0° C. The mixture was stirred at 25° C. for 3 hours. LCMSshowed the reaction was complete. The mixture was diluted with asaturated aqueous solution of ammonium chloride (50 mL) and extractedwith ethyl acetate (30 mL×3). The combined organic layers were washedwith brine (60 mL×2), dried with anhydrous sodium sulfate, filtered andconcentrated under vacuum. The resulting residue was purified bypreparative reverse phase HPLC to give tert-butylN-[4-[4-[2-(2-benzyloxyethoxy)ethylsulfonyl]piperazin-1-yl]cyclohexyl]carbamate(700 mg, 1.33 mmol, 49% yield) as a colorless oil. MS (ESI) m/z: 526.2[M+H]⁺.

Step 2:

To a solution of tert-butylN-[4-[4-[2-(2-benzyloxyethoxy)ethylsulfonyl]piperazin-1-yl]cyclohexyl]carbamate (650 mg, 1.24 mmol, 1 eq) in tetrahydrofuran (10mL) and methanol (10 mL) was added palladium on activated carboncatalyst (100 mg, 1.24 mmol, 10% purity, 1.00 eq) under nitrogen. Thesuspension was degassed under vacuum and purged with hydrogen severaltimes. The mixture was stirred under hydrogen (15 psi) at 25° C. for 12hours. Thin layer chromatography (dichloromethane:methanol=10:1) showedthe reaction was complete. The mixture was filtered and the filtrate wasconcentrated under vacuum to afford tert-butylN-[4-[4-[2-(2-hydroxyethoxy)ethylsulfonyl]piperazin-1-yl]cyclohexyl]carbamate(420 mg, 0.96 mmol, 77% yield) as a colorless oil which was used in thenext step without further purification.

Step 3:

To a solution of tert-butylN-[4-[4-[2-(2-hydroxyethoxy)ethylsulfonyl]piperazin-1-yl]cyclohexyl]carbamate(450 mg, 1.03 mmol, 1 eq) in dichloromethane (3 mL) was addedhydrochloric acid in dioxane (5 mL). The mixture was stirred at 25° C.for 0.5 hour. Thin layer chromatography (dichloromethane:methanol=10:1)indicated completion of the reaction. The mixture was concentrated underreduced pressure to obtain2-[2-[4-(4-aminocyclohexyl)piperazin-1-yl]sulfonylethoxy]ethanol (320mg, 0.95 mmol, 92% yield) as a white solid. The crude product was usedwithout further purification in subsequent reactions.

Step 4:

To a solution of2-[2-[4-(4-aminocyclohexyl)piperazin-1-yl]sulfonylethoxy]ethanol (320mg, 0.95 mmol, 1 eq) in dimethylacetamide (10 mL) was addedN,N-diisopropylethylamine (986 mg, 7.63 mmol, 8 eq) and4-chloroquinazoline-6-carbonitrile (180 mg, 0.95 mmol, 1 eq). Themixture was stirred at 25° C. for 12 hours. LCMS analysis of an aliquotindicated the reaction was complete. The mixture was concentrated underreduced pressure. The residue was purified by preparative reverse phaseHPLC to give4-(((1r,4r)-4-(4-((2-(2-hydroxyethoxy)ethyl)sulfonyl)piperazin-1-yl)cyclohexyl)amino)quinazoline-6-carbonitrile(11 mg, 0.022 mmol, 4.72% yield) as a colorless oil. MS (ESI) m/z: 489.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ: 8.94 (d, J=1.2 Hz, 1H), 8.55 (s,1H), 8.29 (d, J=7.2 Hz, 1H), 8.05 (dd, J=1.6, 8.8 Hz, 1H), 7.76 (d,J=8.8 Hz, 1H), 4.68-4.57 (m, 1H), 4.19 (s, 1H), 3.74 (t, J=6.0 Hz, 2H),3.52-3.49 (m, 2H), 3.46 (d, J=4.8 Hz, 2H), 3.29 (s, 2H), 3.15 (d, J=2.4Hz, 4H), 2.58 (s, 4H), 2.09-2.00 (m, 2H), 1.91-1.80 (m, 2H), 1.46-1.31(m, 4H), 1.20-1.11 (m, 1H).

4-(((1s,4s)-4-(4-((2-(2-hydroxyethoxy)ethyl)sulfonyl)piperazin-1-yl)cyclohexyl)amino)quinazoline-6-carbonitrile(85 mg, 0.17 mmol, 36.48% yield) was obtained as a white solid. ¹H NMR(400 MHz, CDCl₃) δ: 8.67 (s, 1H), 8.26 (s, 1H), 7.93-7.80 (m, 2H), 6.60(d, J=8.0 Hz, 1H), 4.66-4.49 (m, 1H), 4.00-3.93 (m, 2H), 3.90-3.84 (m,2H), 3.73-3.65 (m, 2H), 3.45 (t, J=4.4 Hz, 4H), 3.36-3.32 (m, 2H),2.76-2.57 (m, 4H), 2.35 (s, 1H), 1.92-1.74 (m, 8H).

Step 5:

To a solution of4-(((1r,4r)-4-(4-((2-(2-hydroxyethoxy)ethyl)sulfonyl)piperazin-1-yl)cyclohexyl)amino)quinazoline-6-carbonitrile (300 mg, 0.61 mmol, 1 eq) indichloromethane (5 mL) was added triethylamine (248 mg, 2.46 mmol, 4eq), 4-dimethylaminopyridine (7 mg, 0.06 mmol, 0.1 eq) andpara-toluensulfonyl chloride (175 mg, 0.09 mmol, 1.5 eq). The mixturewas stirred at 25° C. for 12 hours. LCMS showed the reaction wascomplete. The mixture was diluted with water (10 mL) and extracted withdichloromethane (10 mL×3). Then the combined organic layers were washedwith brine (20 mL×2), dried with anhydrous sodium sulfate, filtered andconcentrated under vacuum. The crude product was purified by preparativereverse phase thin layer chromatography (dichloromethane:methanol=20:1)to give2-(2-((4-((1r,4r)-4-((6-cyanoquinazolin-4-yl)amino)cyclohexyl)piperazin-1-yl)sulfonyl)ethoxy)ethyl4-methylbenzenesulfonate (150 mg, 0.23 mmol, 38% yield) as a colorlessoil. MS (ESI) m/z: 643.0 [M+H]⁺.

Step 6:

To a solution of2-(2-((4-((1r,4r)-4-((6-cyanoquinazolin-4-yl)amino)cyclohexyl)piperazin-1-yl)sulfonyl)ethoxy)ethyl4-methylbenzenesulfonate (150 mg, 0.23 mmol, 1 eq) inN,N-dimethylformamide (3 mL) was added2-(2,6-dioxo-3-piperidyl)-5-hydroxy-isoindoline-1,3-dione (76 mg, 0.28mmol, 1.2 eq) and potassium carbonate (64 mg, 0.46 mmol, 2 eq). Themixture was stirred at 60° C. for 2 hours. LCMS showed the reaction wascompleted. The mixture was diluted with water (10 mL) and extracted withethyl acetate (10 mL×3). The combined organic layers were washed withbrine (20 mL×3), dried with anhydrous sodium sulfate, filtered andconcentrated in vacuum. The crude product was purified by preparativereverse phase thin layer chromatography (dichloromethane:methanol=10:1)to give4-(((1r,4r)-4-(4-((2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)ethoxy)ethyl)sulfonyl)piperazin-1-yl)cyclohexyl)amino)quinazoline-6-carbonitrile(29.9 mg, 0.04 mmol, 16% yield, 96% purity) as a white solid. MS (ESI)m/z: 745.3 [M+H]⁺. ¹H NMR: (400 MHz, DMSO-d₆) δ: 11.09 (s, 1H), 8.93 (d,J=1.6 Hz, 1H), 9.02-8.86 (m, 1H), 8.55 (s, 1H), 8.26 (d, J=7.6 Hz, 1H),8.05 (dd, J=1.6, 8.8 Hz, 1H), 7.84 (d, J=8.4 Hz, 1H), 7.76 (d, J=8.8 Hz,1H), 7.47 (d, J=2.0 Hz, 1H), 7.39 (dd, J=2.0, 8.4 Hz, 1H), 5.10 (dd,J=5.6, 12.8 Hz, 1H), 4.33 (dd, J=3.2, 5.2 Hz, 2H), 4.19-4.02 (m, 1H),3.89-3.72 (m, 4H), 3.33 (s, 2H), 3.15 (d, J=4.8 Hz, 4H), 2.91-2.79 (m,1H), 2.53 (d, J=6.4 Hz, 4H), 2.52 (s, 2H), 2.40-2.28 (m, 1H), 2.05-1.93(m, 3H), 1.77 (d, J=10.0 Hz, 2H), 1.46-1.28 (m, 4H).

The following compounds may be prepared in an analogous fashion as theexemplary synthesis described for Exemplary Compound 34.

Exemplary Compound [M + H]⁺

745.56

789.43

789.43

833.45

833.45

877.49

877.48

A compound of formula I may be reacted with a reagent II (commerciallyavailable or readily prepared using standard reaction techniques knownto one skilled in the art) where Y is an appropriate leaving group (e.g.OMs, OTs, Cl, Br, etc.) under etherification conditions to produce acompound of formula III, wherein L represents an optional linker orportion of a linker. Suitable reactions conditions for O-alkylationentail the use of a base, e.g. NaH or potassium carbonate in a solventsuch as DMF at 60° C. A compound of formula III can be reacted with2-(2,6-dioxo-3-piperidyl)-5-hydroxy-isoindoline-1,3-dione to providecompounds of formula IV using suitable reaction conditions for analkylation reaction, e.g. diisopropylethylamine, potassium iodide, DMSOor acetonitrile, 80° C.

Exemplary Synthesis of Exemplary Compound 42N-(1-((1s,4s)-4-(13-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)-2,5,8,11-tetraoxatridecyl)cyclohexyl)-5-(piperidin-1-ylmethyl)-1H-benzo[d]imidazol-2-yl)-3-(trifluoromethyl)benzamide

Step 1:

To a solution of 4-fluoro-3-nitro-benzaldehyde (12 g, 70.96 mmol, 1 eq)and acetic acid (12.78 g, 212.88 mmol, 12.18 mL, 3 eq) in1,2-dichloroethane (200 mL) was added a solution of piperidine (6.65 g,78.06 mmol, 7.71 mL, 1.1 eq) in 1,2-dichloroethane (50 mL) at 0° C. for1 hour. Then sodium borohydride acetate (60.16 g, 283.84 mmol, 4 eq) wasadded to the stirring solution. The mixture was stirred at 0 to 25° C.for 9 hours. The reaction mixture was quenched by addition water (400mL) at 0° C., and then washed with ethyl acetate (100 mL×2). The aqueouslayer was adjusted to pH=8 by the addition of a saturated aqueoussolution of sodium bicarbonate, extracted with ethyl acetate (200 mL×2),dried over sodium sulfate, filtered and concentrated under reducedpressure to afford crude 1-[(4-fluoro-3-nitro-phenyl)methyl]piperidine(8 g, 33.58 mmol, 47% yield), obtained as a red oil and used in asubsequent reaction without further purification. MS(ESI) m/z: 239.1[M+H]⁺.

Step 2:

To a solution of 1-[(4-fluoro-3-nitro-phenyl)methyl]piperidine (6.8 g,28.54 mmol, 1 eq) in dimethyl sulfoxide (35 mL) was addeddiisopropylethylamine (14.75 g, 114.16 mmol, 19.88 mL, 4 eq) and ethyl(1s,4s)-4-aminocyclohexanecarboxylate, Intermediate 1 (5.93 g, 28.54mmol, 1 eq, hydrogen chloride). The mixture was stirred at 110° C. for10 hours. The reaction mixture was quenched by the addition of water(200 mL) at 0° C., and then extracted with ethyl acetate (200 mL×2). Thecombined organic layers were washed with a brine solution (200 mL×2),dried over anhydrous sodium sulfate, filtered and concentrated underreduced pressure to provide crude ethyl(1s,4s)-4-((2-nitro-4-(piperidin-1-ylmethyl)phenyl)amino)cyclohexane-1-carboxylate(10 g, 25.67 mmol, 90% yield), obtained as a yellow solid and used as isin the next transformation without further purification. MS (ESI) m/z:390.2 [M+H]⁺.

Step 3:

To a solution of ethyl(1s,4s)-4-((2-nitro-4-(piperidin-1-ylmethyl)phenyl)amino)cyclohexane-1-carboxylate(4.5 g, 11.55 mmol, 1 eq) in ethanol (100 mL) was added zinc (15.11 g,231.07 mmol, 20 eq) and ammonium chloride (12.36 g, 231.07 mmol, 20 eq).The mixture was stirred at 55° C. for 10 hours. The reaction mixture wasfiltered, the solid was washed with ethanol (50 mL×2), the filtrate wasconcentrated under reduced pressure to give a residue. The residue wasdiluted with a saturated aqueous solution of sodium bicarbonate (50 mL)and extracted with ethyl acetate (50 mL×2). The combined organic layerswere dried over anhydrous sodium sulfate, filtered and concentratedunder reduced pressure to afford crude ethyl(1s,4s)-4-((2-amino-4-(piperidin-1-ylmethyl)phenyl)amino)cyclohexane-1-carboxylate(4 g, 11.13 mmol, 96% yield), obtained as a black oil and used in thesubsequent reaction without further purification. MS (ESI) m/z: 275.2[M−84]⁺.

Step 4:

To a solution of cyanic bromide (1.41 g, 13.35 mmol, 982.10 μL, 1.2 eq)in ethanol (20 mL) was added a solution of ethyl(1s,4s)-4-((2-amino-4-(piperidin-1-ylmethyl)phenyl)amino)cyclohexane-1-carboxylate(4 g, 11.13 mmol, 1 eq) in ethanol (40 mL) at 0° C. The mixture wasstirred at 0-25° C. for 10 hours. The reaction mixture was quenched byaddition of a saturated aqueous solution of sodium bicarbonate (20 mL)at 25° C., and then extracted with ethyl acetate (100 mL×2). Thecombined organic layers were dried over anhydrous sodium sulfate,filtered and concentrated under reduced pressure to give a residue. Theresidue was purified by preparative HPLC. The appropriate fractions werepooled and the pH was adjusted to pH=8 by the addition of a saturatedaqueous solution of sodium bicarbonate (20 mL) at 25° C. The mixture wasextracted with ethyl acetate (100 mL×2), concentrated under reducedpressure to give ethyl(1s,4s)-4-(2-amino-5-(piperidin-1-ylmethyl)-1H-benzo[d]imidazol-1-yl)cyclohexane-1-carboxylate(1 g, 2.60 mmol, 23% yield) as a white solid. MS (ESI) m/z: 385.3.[M+H]⁺.

Step 5:

To a solution of 3-(trifluoromethyl)benzoic acid (543.88 mg, 2.86 mmol,1.1 eq) in N,N-dimethylformamide (10 mL) was added HATU (1.19 g, 3.12mmol, 1.2 eq) and N,N-diisopropylethylamine (1.34 g, 10.40 mmol, 1.81mL, 4 eq), ethyl(1s,4s)-4-(2-amino-5-(piperidin-1-ylmethyl)-1H-benzo[d]imidazol-1-yl)cyclohexane-1-carboxylate(1 g, 2.60 mmol, 1 eq). The mixture was stirred at 25° C. for 1 hour.The reaction mixture was quenched by the addition of water (10 mL) at25° C., and then diluted with ethyl acetate (20 mL) and extracted withethyl acetate (20 mL×2). The combined organic layers were washed with abrine solution (20 mL×2), dried over anhydrous sodium sulfate, filteredand concentrated under reduced pressure. The resulting residue waspurified by silica gel column chromatography (gradient from 50: to 5:1ethyl acetate:methanol) to afford ethyl(1s,4s)-4-(5-(piperidin-1-ylmethyl)-2-(3-(trifluoromethyl)benzamido)-1H-benzo[d]imidazol-1-yl)cyclohexane-1-carboxylate (1.2 g,2.16 mmol, 83% yield) as a white solid. MS (ESI) m/z: 557.3. [M+H]⁺.

Step 6:

To a solution of ethyl(1s,4s)-4-(5-(piperidin-1-ylmethyl)-2-(3-(trifluoromethyl)benzamido)-1H-benzo[d]imidazol-1-yl)cyclohexane-1-carboxylate(1.2 g, 2.16 mmol, 1 eq) in tetrahydrofuran (10 mL) was addeddiisobutylaluminumhydride (1 M, 4.74 mL, 2.2 eq) at 0 C. The mixture wasstirred at 0 to 25° C. for 12 hours. The reaction mixture was quenchedby the addition of a saturated aqueous solution of ammonium chloride (50mL) at 0° C., and then diluted with ethyl acetate (10 mL) and extractedwith ethyl acetate (20 mL×3). The combined organic layers were washedwith brine (20 mL×2), dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure. The resulting residue was purifiedby silica gel column chromatography (eluted with petroleum ether:ethylacetate=1:1 to 0:1) to affordN-(1-((1s,4s)-4-(hydroxymethyl)cyclohexyl)-5-(piperidin-1-ylmethyl)-1H-benzo[d]imidazol-2-yl)-3-(trifluoromethyl)benzamide(0.5 g, 777 μmol, 36% yield, 80% purity) as a yellow oil. MS (ESI) m/z:515.1 [M+H]⁺.

Step 7:

To a solution ofN-(1-((1s,4s)-4-(hydroxymethyl)cyclohexyl)-5-(piperidin-1-ylmethyl)-1H-benzo[d]imidazol-2-yl)-3-(trifluoromethyl)benzamide(0.5 g, 971 μmol, 1 eq) in dimethylformamide (2 mL) was added sodiumhydride (155.5 mg, 3.89 mmol, 60% purity, 4 eq) at 0° C. After stirringat 0° C. for 0.5 hour,1-(2-bromoethoxy)-2-[2-(2-bromoethoxy)ethoxy]ethane (932.8 mg, 2.91mmol, 73.1 μL, 3 eq) was added to the reaction. The mixture was stirredat 0 to 25° C. for 1.5 hours. The reaction mixture was concentrated togive a residue which was purified by preparative HPLC to affordN-(1-((1s,4s)-4-(13-bromo-2,5,8,11-tetraoxatridecyl)cyclohexyl)-5-(piperidin-1-ylmethyl)-1H-benzo[d]imidazol-2-yl)-3-(trifluoromethyl)benzamide(0.2 g, 238.83 μmol, 25% yield, 90% purity) obtained as a yellow oil. MS(ESI) m/z: 753.3 [M+H]⁺.

Step 8:

To a solution ofN-(1-((1s,4s)-4-(13-bromo-2,5,8,11-tetraoxatridecyl)cyclohexyl)-5-(piperidin-1-ylmethyl)-1H-benzo[d]imidazol-2-yl)-3-(trifluoromethyl)benzamide(0.15 g, 199.02 μmol, 1 eq) in dimethylformamide (3 mL) was addedpotassium carbonate (82.52 mg, 597.06 μmol, 3 eq) and2-(2,6-dioxo-3-piperidyl)-5-hydroxy-isoindoline-1,3-dione (81.87 mg,298.53 μmol, 1.5 eq). The mixture was allowed to stir at 60° C. for 12hours. The reaction mixture was concentrated to give a residue which waspurified by preparative HPLC to affordN-(1-((1s,4s)-4-(13-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)-2,5,8,11-tetraoxatridecyl)cyclohexyl)-5-(piperidin-1-ylmethyl)-1H-benzo[d]imidazol-2-yl)-3-(trifluoromethyl)benzamide(19.1 mg, 19.36 μmol, 10% yield, 96% purity) obtained as a white solid.MS (ESI) m/z: 947.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d6) δ ppm 12.83 (br s,1H) 11.12 (s, 1H) 8.50 (d, J=7.88 Hz, 1H) 8.43 (s, 1H) 8.30 (s, 1H) 7.90(br d, J=7.64 Hz, 1H) 7.81 (d, J=8.26 Hz, 1H) 7.74 (t, J=7.68 Hz, 1H)7.56 (d, J=8.38 Hz, 1H) 7.51 (s, 1H) 7.43 (d, J=2.14 Hz, 1H) 7.34 (dd,J=8.32, 2.31 Hz, 1H) 7.15-7.24 (m, 1H) 5.12 (dd, J=12.88, 5.38 Hz, 1H)4.72 (br s, 1H) 4.24-4.32 (m, 2H) 3.72-3.79 (m, 2H) 3.68 (br d, J=7.50Hz, 2H) 3.45-3.59 (m, 18H) 1.40 (br s, 2H) 2.89 (ddd, J=17.40, 14.13,5.50 Hz, 1H) 2.52-2.63 (m, 3H) 2.30-2.35 (m, 4H) 2.00-2.09 (m, 2H)1.86-1.96 (m, 2H) 1.60-1.77 (m, 4H) 1.49 (br d, J=5.00 Hz, 4H).

The following compounds may be prepared in an analogous fashion as theexemplary synthesis described for Exemplary Compound 42.

Exemplary Compound MS

903.66 Exemplary Compound 43

859.62 Exemplary Compound 44

Exemplary Synthesis of Exemplary Compound 45N-(1-((1s,4s)-4-((2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)ethoxy)methyl)cyclohexyl)-5-fluoro-1H-benzo[d]imidazol-2-yl)-3-(trifluoromethyl)benzamide

Step 1:

A solution of ethyl (1s,4s)-4-aminocyclohexanecarboxylate, Intermediate1 (22 g, 105.92 mmol, 1 eq, hydrochloride), 1,4-difluoro-2-nitro-benzene(16.85 g, 105.92 mmol, 11.46 mL, 1.0 eq) and diisopropylethylamine(67.29 g, 520.67 mmol, 90.69 mL, 4.92 eq) in dimethylsulfoxide (200 mL)was stirred at 100° C. for 2.5 hours. LCMS analysis of the crudereaction mixture showed the reaction reached completion. The reactionmixture was poured into water (1000 mL). The mixture was extracted withethyl acetate (1000 mL×3). The combined organic phase was washed withbrine (1000 mL×3), dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure to afford a residue. The crudeproduct was purified by re-crystallization from petroleum ether (100 mL)at 0° C. to afford ethyl (1s,4s)-4-((4-fluoro-2-nitrophenyl)amino)cyclohexane-1-carboxylate (29 g, 93.45 mmol, 88% yield) as a red solid.¹H NMR (400 MHz, CDCl₃) δ=1.28 (t, J=7.15 Hz, 3H), 1.71-1.90 (m, 6H),1.93-2.06 (m, 2H), 2.47-2.57 (m, 1H), 3.68 (br s, 1H), 4.17 (q, J=6.8Hz, 2H), 6.84 (dd, J=9.6, 4.8 Hz, 1H), 7.23 (ddd, J=9.6, 6.8, 2.8 Hz,1H), 7.90 (dd, J=9.6, 3.2 Hz, 1H), 8.14 (br d, J=6.4 Hz, 1H).

Step 2:

To a solution of ethyl(1s,4s)-4-((4-fluoro-2-nitrophenyl)amino)cyclohexane-1-carboxylate (2 g,6.44 mmol, 1 eq) in ethyl alcohol (40 mL) was added palladium on carbon(0.2 g, 10% purity) under nitrogen atmosphere. The suspension wasdegassed and purged with a hydrogen atmosphere 3 times. The mixture wasstirred under hydrogen (15 psi) at 25° C. for 3 hours. LCMS analysisindicated the reaction had reached completion. The suspension wasfiltered, and the filtrate was concentrated under reduced pressure toyield crude ethyl(1s,4s)-4-((2-amino-4-fluorophenyl)amino)cyclohexane-1-carboxylate (1.7g, 6.06 mmol, 94% yield), obtained as a red oil and used in a subsequentreaction without further purification. ¹H NMR (400 MHz, CDCl₃) δ=1.27(t, J=7.15 Hz, 3H), 1.59-1.84 (m, 6H), 1.91-2.10 (m, 2H), 2.49 (tt,J=7.6, 3.6 Hz, 1H), 2.60-3.12 (m, 1H), 3.26-3.40 (m, 1H), 3.48-3.82 (m,2H), 4.11-4.26 (m, 2H), 6.38-6.49 (m, 2H), 6.60 (dd, J=8.4, 5.6 Hz, 1H).

Step 3:

A solution of ethyl(1s,4s)-4-((2-amino-4-fluorophenyl)amino)cyclohexane-1-carboxylate (1.7g, 6.06 mmol, 1 eq) in methyl alcohol (17 mL) was treated with asolution of bromine ethyl cyanide (963.5 mg, 9.10 mmol, 669.1 μL, 1.5eq) in acetonitrile (2 mL) and water (2 mL). The reaction mixture wasstirred at 50° C. for 12 hours. LCMS analysis of the reaction mixtureshowed the reaction was complete. The reaction mixture was diluted withwater (30 mL). The pH was adjusted to pH=8 with sodium carbonate, andthe mixture was extracted with ethyl acetate (30 mL×3). The combinedorganic layers were washed with brine (20 mL×3), dried over anhydroussodium sulfate, filtered and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography to afford ethyl(1s,4s)-4-(2-amino-5-fluoro-1H-benzo[d]imidazol-1-yl)cyclohexane-1-carboxylate(1.7 g, 5.57 mmol, 91% yield) as a yellow solid. MS (ESI) m/z: 306.1[M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 1.32 (t, J=6.8 Hz, 3H), 1.64 (tt,J=14.0, 4.4 Hz, 2H), 1.73-1.85 (m, 2H), 2.27 (br dd, J=14.0, 1.6 Hz,2H), 2.44 (qd, J=13.2, 4.0 Hz, 2H), 2.65-2.81 (m, 1H), 4.00 (tt, J=12.8,4.8 Hz, 1H), 4.24 (q, J=7.2 Hz, 2H), 5.28 (br s, 2H), 6.68-6.81 (m, 1H),7.03-7.17 (m, 2H).

Step 4:

To a solution of 3-(trifluoromethyl)benzoic acid (622.63 mg, 3.27 mmol,1 eq) in N,N-dimethylformamide (10 mL) was added HATU (1.49 g, 3.93mmol, 1.2 eq) and N,N-diisopropylethylamine (1.27 g, 9.82 mmol, 1.71 mL,3 eq). After stirring at 25° C. for 10 min, ethyl(1s,4s)-4-(2-amino-5-fluoro-1H-benzo[d]imidazol-1-yl)cyclohexane-1-carboxylate(1.0 g, 3.27 mmol, 1 eq) was added. The resulting mixture was stirred at25° C. for 11 hours and 50 minutes. LCMS analysis of an aliquotindicated complete conversion. The mixture was poured into ice-water (60mL). The aqueous phase was extracted with ethyl acetate (30 mL×3). Thecombined organic phase was washed with brine (20 mL×2), dried withanhydrous sodium sulfate, filtered and concentrated under vacuum. Theresidue was purified by silica gel column chromatography (eluted with agradient from 10 to 5:1 petroleum ether:ethyl acetate) to afford ethyl(1s,4s)-4-(5-fluoro-2-(3-(trifluoromethyl)benzamido)-1H-benzo[d]imidazol-1-yl)cyclohexane-1-carboxylate(1.3 g, 2.72 mmol, 83% yield) as a gray solid. MS (ESI) m/z: 478.1[M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ=1.34 (t, J=7.15 Hz, 3H), 1.79-1.91 (m,4H), 2.38 (br d, J=13.6 Hz, 2H), 2.47-2.66 (m, 2H), 2.84 (br s, 1H),4.28 (q, J=7.2 Hz, 2H), 4.97 (ddd, J=12.4, 8.8, 4.0 Hz, 1H), 6.98 (td,J=9.2, 2.4 Hz, 1H), 7.05 (dd, J=8.0, 2.4 Hz, 1H), 7.43 (dd, J=8.8, 4.4Hz, 1H), 7.58 (t, J=7.6 Hz, 1H), 7.74 (d, J=7.6 Hz, 1H), 8.51 (d, J=8.0Hz, 1H), 8.57 (s, 1H), 12.70 (br s, 1H).

Step 5:

To a solution of ethyl(1s,4s)-4-(5-fluoro-2-(3-(trifluoromethyl)benzamido)-1H-benzo[d]imidazol-1-yl)cyclohexane-1-carboxylate(0.6 g, 1.26 mmol, 1 eq) in tetrahydrofuran (12 mL) was addeddiisobutylaluminium hydride (1 M, 2.51 mL, 2 eq) at 0° C. The reactionmixture was stirred at 25° C. for 12 hours. LCMS analysis showed thereaction was complete. The reaction mixture was quenched with water (2mL) at 0° C., diluted with ethyl acetate (80 mL), and anhydrous sodiumsulfate (10 g) was added. The mixture was stirred at 25° C. for 15minutes and filtered. The filtrate was concentrated under reducedpressure. The resulting residue was purified by silica gel columnchromatography (eluted with a gradient from 5 to 3:1 petroleumether:ethyl acetate) to afford N-(5-fluoro-1-((1s,4s)-4-(hydroxymethyl)cyclohexyl)-1H-benzo[d]imidazol-2-yl)-3-(trifluoromethyl)benzamide(0.5 g, 1.14 mmol, 90% yield, 99% purity), obtained as a white solid. MS(ESI) m/z: 436.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ=1.58-1.87 (m, 5H),1.97-2.18 (m, 3H), 2.48-2.69 (m, 2H), 3.96 (br d, J=7.2 Hz, 2H),4.59-4.80 (m, 1H), 6.99 (td, J=9.2, 2.4 Hz, 1H), 7.07 (dd, J=8.0, 2.0Hz, 1H), 7.31 (dd, J=8.8, 4.2 Hz, 1H), 7.53-7.64 (m, 1H), 7.75 (br d,J=7.6 Hz, 1H), 8.47 (br d, J=7.8 Hz, 1H), 8.59 (s, 1H), 12.24-13.35 (m,1H).

Step 6:

To a solution ofN-(5-fluoro-1-((1s,4s)-4-(hydroxymethyl)cyclohexyl)-1H-benzo[d]imidazol-2-yl)-3-(trifluoromethyl)benzamide(0.7 g, 1.61 mmol, 1 eq) and diacetoxyrhodium (53.3 mg, 241.15 μmol,0.15 eq) in dichloromethane (20 mL) was added ethyl 2-diazoacetate (1.28g, 11.25 mmol, 7 eq) at 0° C. under nitrogen. The mixture was stirred at25° C. for 12 hours. LCMS analysis showed the reaction was complete. Themixture was concentrated and the resulting residue was purified bysilica gel column chromatography (petroleum ether/ethyl acetate=5/1 to2/1) to afford ethyl2-(((1s,4s)-4-(5-fluoro-2-(3-(trifluoromethyl)benzamido)-1H-benzo[d]imidazol-1-yl)cyclohexyl)methoxy)acetate (0.6 g, 1.15 mmol, 71% yield) as a light brown oil. MS(ESI) m/z: 522.2 [M+H]⁺.

Step 7:

To a solution of ethyl2-(((1s,4s)-4-(5-fluoro-2-(3-(trifluoromethyl)benzamido)-1H-benzo[d]imidazol-1-yl)cyclohexyl)methoxy)acetate(0.3 g, 575.3 μmol, 1 eq) in dichloromethane (8 mL) was addeddiisobutylaluminium hydride (1 M, 2.30 mL, 4 eq) dropwise at −78° C. Thereaction was stirred at 25° C. for 12 hours. Thin layer chromatography(petroleum ether/ethyl acetate=3:1) analysis indicated the reaction wascomplete. The reaction mixture was quenched with a saturated aqueoussolution of ammonium chloride (3 mL) at −78° C., diluted with ethylacetate (50 mL), dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure. The resulting residue was purifiedby silica gel column chromatography (eluted with a gradient from 10 to5:1 petroleum ether:ethyl acetate) to affordN-(5-fluoro-1-((1s,4s)-4-((2-hydroxyethoxy)methyl)cyclohexyl)-1H-benzo[d]imidazol-2-yl)-3-(trifluoromethyl)benzamide(0.15 g, 312.8 μmol, 54% yield), obtained as a white solid.

Step 8:

To a mixture ofN-(5-fluoro-1-((1s,4s)-4-((2-hydroxyethoxy)methyl)cyclohexyl)-1H-benzo[d]imidazol-2-yl)-3-(trifluoromethyl)benzamide(40 mg, 83.43 μmol, 1 eq),2-(2,6-dioxo-3-piperidyl)-5-hydroxy-isoindoline-1,3-dione (30 mg, 109.4μmol, 1.31 eq) and triphenylphosphine (43.76 mg, 166.85 umol, 2 eq) intetrahydrofuran (2 mL) was added dropwise diisopropyl azodicarboxylate(33.74 mg, 166.85 μmol, 32.44 μL, 2 eq) in tetrahydrofuran (0.5 mL) at25° C. The mixture was stirred at 25° C. for 0.5 hour, then heated to50° C. for 11.5 hours. LCMS analysis of an aliquot indicated formationof the desired compound. The mixture was concentrated under reducedpressure and the resulting residue was purified by semi-preparativereverse phase HPLC to obtainN-(1-((1s,4s)-4-((2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)ethoxy)methyl)cyclohexyl)-5-fluoro-1H-benzo[d]imidazol-2-yl)-3-(trifluoromethyl)benzamide(6.2 mg, 8.26 umol, 9% yield, 98% purity) as a white solid. MS (ESI)m/z: 736.3 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ=1.72-1.84 (m, 4H),2.00-2.11 (m, 2H), 2.12-2.29 (m, 2H), 2.48-2.66 (m, 2H), 2.67-2.98 (m,3H), 3.83 (d, J=7.2 Hz, 2H), 3.89-3.99 (m, 2H), 4.25-4.36 (m, 2H),4.57-4.74 (m, 1H), 4.96 (dd, J=12.4, 5.2 Hz, 1H), 6.93-7.02 (m, 1H),7.09 (dd, J=8.0, 2.4 Hz, 1H), 7.22 (dd, J=8.4, 2.4 Hz, 1H), 7.28-7.33(m, 1H), 7.38 (d, J=2.4 Hz, 1H), 7.54-7.65 (m, 1H), 7.71-7.80 (m, 2H),8.04 (s, 1H), 8.48 (d, J=7.6 Hz, 1H), 8.57 (s, 1H), 12.55-12.94 (m, 1H).

A compound of formula I may be reacted with a reagent II (commerciallyavailable or readily prepared using standard reaction techniques knownto one skilled in the art) where Y is an appropriate leaving group (e.g.OMs, OTs, Cl, Br, etc.) under O-alkylation conditions to produce acompound of formula III, wherein L represents an optional linker orportion of a linker. A compound of formula III can be reacted with2-(2,6-dioxo-3-piperidyl)-5-hydroxy-isoindoline-1,3-dione to providecompounds of formula IV using suitable reaction conditions for analkylation reaction, e.g. diisopropylethylamine, potassium iodide, DMSOor acetonitrile, 80° C.

Exemplary Synthesis of Exemplary Compound 46N-(1-((1s,4s)-4-((2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)ethoxy)ethoxy)methyl)cyclohexyl)-5-fluoro-1H-benzo[d]imidazol-2-yl)-3-(trifluoromethyl)benzamide

Step 1:

To a stirring mixture of sodium hydride (162.67 mg, 4.07 mmol, 60%purity, 2.21 eq) in N,N-dimethylformamide (8 mL) was added a solution ofN-(5-fluoro-1-((1s,4s)-4-(hydroxymethyl)cyclohexyl)-1H-benzo[d]imidazol-2-yl)-3-(trifluoromethyl)benzamide(Example 43 Intermediate) (0.8 g, 1.84 mmol, 1 eq) inN,N-dimethylformamide (0.5 mL) dropwise at 0° C. under nitrogen. Afteraddition, the mixture was stirred at 25° C. for 0.5 hour, after which1-bromo-2-(2-bromoethoxy)ethane (520.0 mg, 2.24 mmol, 281.1 μL, 1.22 eq)was added to the mixture at 0° C. The mixture was stirred at 25° C. for11.5 hours. LCMS analysis showed some formation of the desired mass. Thereaction mixture was quenched with acetic acid (1.5 mL) at 0° C.,diluted with water (30 mL) and extracted with ethyl acetate (3×30 mL).The organic layers were combined washed with brine (2×20 mL), dried withanhydrous sodium sulfate, filtered and concentrated under vacuum to givea residue. The residue was purified by silica gel column chromatography(petroleum ether/ethyl acetate=5/1) and then further purified bypreparative thin-layer chromatography (petroleum ether/ethylacetate=2/1) to affordN-(1-((1s,4s)-4-((2-(2-bromoethoxy)ethoxy)methyl)cyclohexyl)-5-fluoro-1H-benzo[d]imidazol-2-yl)-3-(trifluoromethyl)benzamide (62 mg, 105.7 μmol, 5% yield) as a brown oil. MS (ESI) m/z:588.2 [M+H]⁺.

Step 2:

To a mixture ofN-(1-((1s,4s)-4-((2-(2-bromoethoxy)ethoxy)methyl)cyclohexyl)-5-fluoro-1H-benzo[d]imidazol-2-yl)-3-(trifluoromethyl)benzamide(60 mg, 102.3 μmol, 1 eq) and2-(2,6-dioxo-3-piperidyl)-5-hydroxy-isoindoline-1,3-dione (37 mg, 134.9μmol, 1.32 eq) in N,N-dimethylformamide (2 mL) was added potassiumcarbonate (56.6 mg, 409.3 μmol, 4 eq). The mixture was stirred at 60° C.for 12 hours. LCMS analysis indicated the reaction to be complete. Themixture was then poured into ice-water (15 mL) and the aqueous phase wasextracted with ethyl acetate (20 mL×3). The combined organic phases werewashed with brine (20 mL×2), dried with anhydrous sodium sulfate,filtered and concentrated under vacuum. The residue was purified bysemi-preparative reverse phase HPLC to affordN-(1-((1s,4s)-4-((2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)ethoxy)ethoxy)methyl)cyclohexyl)-5-fluoro-1H-benzo[d]imidazol-2-yl)-3-(trifluoromethyl)benzamide(9.1 mg, 11.5 μmol, 11% yield, 99% purity) as an off-white solid. MS(ESI) m/z: 780.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ=1.71-1.84 (m, 4H),2.02-2.09 (m, 2H), 2.11-2.24 (m, 2H), 2.47-2.64 (m, 2H), 2.68-2.96 (m,3H), 3.71-3.82 (m, 6H), 3.87-3.95 (m, 2H), 4.18-4.26 (m, 2H), 4.62-4.80(m, 1H), 4.97 (dd, J=12.23, 5.2 Hz, 1H), 6.95 (td, J=8.8, 2.4 Hz, 1H),7.03-7.09 (m, 1H), 7.14 (dd, J=8.4, 2.0 Hz, 1H), 7.23 (d, J=2.0 Hz, 1H),7.32 (dd, J=8.8, 4.2 Hz, 1H), 7.55-7.62 (m, 1H), 7.68-7.79 (m, 2H),8.11-8.19 (m, 1H), 8.48 (d, J=8.0 Hz, 1H), 8.56 (s, 1H), 12.43-12.98 (m,1H).

The following compounds may be prepared in an analogous fashion as theexemplary synthesis described for Exemplary Compound 46.

Exemplary Compound [M + H]⁺

824.60 Exemplary Compound 47

868.64 Exemplary Compound 48

A compound of formula I may be reacted with a reagent II (commerciallyavailable or readily prepared using standard reaction techniques knownto one skilled in the art) where Y is an appropriate leaving group (e.g.OMs, OTs, Cl, Br, etc.) and X is either an appropriate leaving group oran aldehyde and wherein L represents an optional linker or portion of alinker. When X is an aldehyde, suitable reaction conditions to provide acompound of formula III entail reductive amination conditions, e.g.2-methylpyridine borane complex, acetic acid, methanol, roomtemperature. A compound of formula III can be reacted with2-(2,6-dioxo-3-piperidyl)-5-hydroxy-isoindoline-1,3-dione to providecompounds of formula IV using suitable reaction conditions for analkylation reaction, e.g. diisopropylethylamine, potassium iodide, DMSOor acetonitrile, 80° C.

Exemplary Synthesis of Exemplary Compound 49N-(1-(3-((2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)ethoxy)ethoxy)ethyl)(methyl)amino)phenyl)-5-fluoro-1H-benzo[d]imidazol-2-yl)-3-(trifluoromethyl)benzamide

Step 1:

To a mixture of 3-nitroaniline (20 g, 144.80 mmol, 36.36 mL, 1 eq) anddi-tert-butyl dicarbonate (31.60 g, 144.80 mmol, 33.26 mL, 1 eq) intetrahydrofuran (300 mL) was added DMAP (19.46 g, 159.28 mmol, 1.1 eq)in portions at 0° C. The mixture was then stirred at 25° C. for 12hours. LCMS analysis of an aliquot indicated consumption of the startingmaterial. The reaction mixture was filtered, and the filtrate wasconcentrated under reduced pressure. The residue was purified by columnchromatography (petroleum ether/ethyl acetate=10/1, Rf=0.3) to affordtert-butyl N-(3-nitrophenyl)carbamate (12 g, 50.37 mmol, 35% yield) as awhite solid. ¹H NMR (400 MHz, DMSO-d₆) δ: 10.02-9.83 (m, 1H), 8.56-8.42(m, 1H), 7.88-7.69 (m, 2H), 7.62-7.47 (m, 1H), 1.57-1.45 (m, 9H).

Step 2:

To a mixture of sodium hydride (2.42 g, 60.44 mmol, 60% purity, 1.2 eq)in dimethylformamide (120 mL) was added a solution of tert-butylN-(3-nitrophenyl)carbamate (12 g, 50.37 mmol, 1 eq) in dimethylformamide(80 mL) portion-wise at 0° C. The mixture was stirred at 0° C. for 30minutes, followed by portion-wise addition of iodomethane (10.72 g,75.55 mmol, 4.70 mL, 1.5 eq) at 0° C. The mixture was then allowed tostir for 2.5 hours at 25° C. LCMS analysis confirmed consumption of thestarting material. The reaction mixture was quenched by the addition ofice water (1000 mL) and the mixture was extracted with ethyl acetate(500 mL×3). The combined organic phase was concentrated under reducedpressure. The resulting residue was purified by column chromatography(petroleum ether/ethyl acetate=5/1, Rf=0.2) to afford tert-butylN-methyl-N-(3-nitrophenyl)carbamate (9 g, 35.68 mmol, 71% yield) as awhite solid. ¹H NMR (400 MHz, DMSO-d₆) δ: 8.21-8.15 (m, 1H), 8.04-7.98(m, 1H), 7.80-7.74 (m, 1H), 7.67-7.59 (m, 1H), 3.28-3.22 (m, 3H),1.46-1.38 (m, 9H).

Step 3:

To a solution of tert-butyl N-methyl-N-(3-nitrophenyl)carbamate (9 g,35.7 mmol, 1 eq) in tetrahydrofuran (70 mL) and methyl alcohol (70 mL)was added Pd/C (1 g, 10% purity). The suspension was degassed undervacuum and purged with hydrogen (1.44 g, 713.53 mmol, 20 eq) severaltimes. The mixture was stirred under hydrogen (15 psi) at 25° C. for 12hours. LCMS analysis indicated consumption of the starting material. Thereaction mixture was filtered and the filtrate was concentrated undervacuum to afford crude tert-butyl N-(3-aminophenyl)-N-methyl-carbamate(7.9 g, 35.54 mmol, 99% yield), obtained as a white solid and used inthe next reaction without further purification. ¹H NMR (400 MHz,DMSO-d₆) δ: 7.00-6.91 (m, 1H), 6.47-6.43 (m, 1H), 6.40-6.34 (m, 2H),5.14-5.02 (m, 2H), 3.12-3.06 (m, 3H), 1.43-1.34 (m, 9H).

Step 4:

To a mixture of tert-butyl N-(3-aminophenyl)-N-methyl-carbamate (7.9 g,35.54 mmol, 1 eq) and 1,4-difluoro-2-nitro-benzene (6.22 g, 39.09 mmol,4.23 mL, 1.1 eq) in dimethylsulfoxide (20 mL) was addeddiisopropylethylamine (9.19 g, 71.08 mmol, 12.38 mL, 2 eq) in oneportion. The mixture was stirred at 100° C. for 12 hours. LCMS analysisshowed complete consumption of the starting material. The reactionmixture was quenched by the addition of ice water (100 mL) and themixture was extracted with ethyl acetate (100 mL×3). The combinedorganic phase was concentrated under reduced pressure and the resultingresidue was purified by column chromatography (petroleum ether/ethylacetate=5/1, Rf=0.2) to afford tert-butylN-[3-(4-fluoro-2-nitro-anilino)phenyl]-N-methyl-carbamate (7.5 g, 20.75mmol, 58% yield) obtained as a white solid. MS (ESI) m/z: 384.1 [M+Na]⁺.

Step 5:

To a solution of tert-butylN-[3-(4-fluoro-2-nitro-anilino)phenyl]-N-methyl-carbamate (2 g, 5.53mmol, 1 eq) in methyl alcohol (20 mL) was added Pd/C (0.2 g, 5.53 mmol,10% purity). The suspension was degassed under vacuum and purged withhydrogen several times. The mixture was stirred under hydrogen (15 psi)at 25° C. for 12 hours. LCMS analysis indicated complete conversion. Thereaction mixture was filtered and the filtrate was concentrated undervacuum. The obtained crude tert-butylN-[3-(2-amino-4-fluoro-anilino)phenyl]-N-methyl-carbamate (1.7 g, 5.13mmol, 93% yield) was used for the next reaction without furtherpurification and was obtained as a white solid. ¹H NMR (400 MHz,DMSO-d6) δ: 7.13-7.08 (m, 1H), 7.08-7.02 (m, 1H), 6.97-6.91 (m, 1H),6.55-6.41 (m, 4H), 6.34-6.26 (m, 1H), 5.13-5.03 (m, 2H), 4.08-4.07 (m,1H), 3.14-3.06 (m, 3H), 1.39-1.29 (m, 9H).

Step 6:

To a mixture of tert-butylN-[3-(2-amino-4-fluoro-anilino)phenyl]-N-methyl-carbamate (5 g, 15.09mmol, 1 eq) in methyl alcohol (84 mL) was added a mixture of cyanogenbromide (2.40 g, 22.63 mmol, 1.66 mL, 1.5 eq) in acetonitrile (6 mL) andwater (6 mL) in portions. The mixture was heated to 50 C and stirred for12 hours. LCMS analysis showed consumption of the starting material. Thereaction mixture was concentrated under vacuum and the resulting residuewas purified by preparative HPLC to afford tert-butylN-[3-(2-amino-5-fluoro-benzimidazol-1-yl)phenyl]-N-methyl-carbamate (2g, 5.61 mmol, 37% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆)δ:7.60-7.52 (m, 1H), 7.49-7.42 (m, 1H), 7.42-7.38 (m, 1H), 7.28-7.23 (m,1H), 7.02-6.97 (m, 1H), 6.85-6.76 (m, 1H), 6.72-6.62 (m, 1H), 6.49-6.38(m, 2H), 3.29-3.22 (m, 3H), 1.48-1.37 (m, 9H).

Step 7:

To a mixture of 3-(trifluoromethyl)benzoic acid (800.2 mg, 4.21 mmol, 1eq), diisopropylethylamine (2.18 g, 16.84 mmol, 2.93 mL, 4 eq) and HATU(1.92 g, 5.05 mmol, 1.2 eq) in dimethylformamide (20 mL) was addedtert-butylN-[3-(2-amino-5-fluoro-benzimidazol-1-yl)phenyl]-N-methyl-carbamate (1.5g, 4.21 mmol, 1 eq) in one portion. The mixture was stirred at 25° C.for 1 hour. LCMS analysis confirmed the reaction to be complete. Thereaction mixture was washed with water (100 mL) and extracted with ethylacetate (50 mL×3). The combined organic phase was concentrated undervacuum and the resulting residue was purified by column chromatography(Petroleum ether/Ethyl acetate=2/1, Rf=0.3) to afford tert-butylN-[3-[5-fluoro-2-[[3-(trifluoromethyl)benzoyl]amino]benzimidazol-1-yl]phenyl]-N-methyl-carbamate(2 g, 3.78 mmol, 90% yield) as a white solid. MS (ESI) m/z: 529.2[M+H]⁺.

Step 8:

A mixture of tert-butylN-[3-[5-fluoro-2-[[3-(trifluoromethyl)benzoyl]amino]benzimidazol-1-yl]phenyl]-N-methyl-carbamate(1 g, 1.89 mmol, 1 eq) and a solution of hydrogen chloride in dioxane (4M, 5 mL, 10.57 eq) was stirred at 25° C. for 1 hour. LCMS analysisconfirmed the reaction to be complete. The reaction mixture wasconcentrated under reduced pressure and the residue was dissolved inethyl acetate (100 mL), and the mixture was washed with a saturatedaqueous solution of sodium bicarbonate to adjust pH to be 8. The organicphase was separated and concentrated under vacuum. CrudeN-[5-fluoro-1-[3-(methylamino)phenyl]benzimidazol-2-yl]-3-(trifluoromethyl)benzamide(770 mg, 1.80 mmol, 95% yield) was obtained as a white solid and used asis in the next reaction without further purification. MS (ESI) m/z:429.1 [M+H]⁺.

Step 9:

To a mixture ofN-[5-fluoro-1-[3-(methylamino)phenyl]benzimidazol-2-yl]-3-(trifluoromethyl)benzamide (300 mg, 700.3 μmol, 1 eq) and 2-[2-(2-oxoethoxy)ethoxy]ethyl4-methylbenzenesulfonate, Intermediate 7 (317.6 mg, 1.05 mmol, 1.5 eq)in methyl alcohol (5 mL) and acetic acid (0.5 mL) was added2-methylpyridine borane complex (112.36 mg, 1.05 mmol, 1.5 eq). Themixture was stirred at 25° C. for 12 hours. LCMS analysis confirmed thereaction to be complete. The reaction mixture was concentrated underreduced pressure and 10% aqueous hydrogen chloride (10 mL) was added tothe residue. The aqueous solution was stirred for 0.5 hour at roomtemperature, and sodium carbonate (ca. 2.5 g) and water (10 mL) wereadded under cooling. The aqueous layer was extracted with ethyl acetate(30 mL×2), and the combined organic layer was washed with brine (15 mL),dried over sodium sulfate, and concentrated. The resulting residue waspurified by column chromatography (petroleum ether/ethyl acetate=1/1,Rf=0.2) to afford2-[2-[2-[3-[5-fluoro-2-[[3-(trifluoromethyl)benzoyl]amino]benzimidazol-1-yl]-N-methyl-anilino]ethoxy]ethoxy]ethyl4-methylbenzenesulfonate (60 mg, 83.95 μmol, 12% yield) as a whitesolid. MS (ESI) m/z: 715.2 [M+H]⁺.

Step 10:

To a mixture of2-[2-[2-[3-[5-fluoro-2-[[3-(trifluoromethyl)benzoyl]amino]benzimidazol-1-yl]-N-methyl-anilino]ethoxy]ethoxy]ethyl4-methylbenzenesulfonate (60 mg, 83.95 μmol, 1 eq) and2-(2,6-dioxo-3-piperidyl)-5-hydroxy-isoindoline-1,3-dione (34.5 mg,125.9 μmol, 1.5 eq) in dimethylformamide (3 mL) was added potassiumcarbonate (46.41 mg, 335.79 μmol, 4 eq). The mixture was heated to 50°C. and stirred for 12 hour. LCMS analysis confirmed the reaction to becomplete. The reaction mixture was washed with water (30 mL) andextracted with ethyl acetate (20 mL×3). The combined organic phase wasconcentrated under reduced pressure and the resulting residue waspurified by preparative HPLC to affordN-[1-[3-[2-[2-[2-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]oxyethoxy]ethoxy]ethyl-methyl-amino]phenyl]-5-fluoro-benzimidazol-2-yl]-3-(trifluoromethyl)benzamide(20.4 mg, 24.98 μmol, 30% yield) as an off-white solid. MS (ESI) m/z:817.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ: 11.10 (s, 1H), 8.35-8.25 (m,2H), 7.83 (br d, J=7.2 Hz, 1H), 7.76 (d, J=8.3 Hz, 1H), 7.69-7.62 (m,1H), 7.44-7.34 (m, 3H), 7.29-7.18 (m, 2H), 7.13-7.02 (m, 1H), 6.96 (brd, J=1.1 Hz, 1H), 6.90-6.80 (m, 2H), 5.10 (dd, J=5.4, 12.8 Hz, 1H),4.25-4.12 (m, 2H), 3.71-3.65 (m, 2H), 3.62-3.45 (m, 10H), 2.96 (s, 3H),2.91-2.82 (m, 1H), 2.63-2.54 (m, 1H), 2.09-1.96 (m, 1H).

The following compounds may be prepared in an analogous fashion as theexemplary synthesis described for Exemplary Compound 49.

Exemplary Compound [M + H]⁺

729.49 Exemplary Compound 50

773.53 Exemplary Compound 51

861.62 Exemplary Compound 52

A compound of formula I where R may be H or OMe may be reacted with areagent II (commercially available or readily prepared using standardreaction techniques known to one skilled in the art) where Y is anappropriate leaving group (e.g. OMs, OTs, Cl, Br, etc.) and X is eitheran appropriate leaving group or an aldehyde and wherein L represents anoptional linker or portion of a linker. When X is an aldehyde, suitablereaction conditions to provide a compound of formula III entailreductive amination conditions, e.g. 2-methylpyridine borane complex orsodium acetoxyborohydride, acetic acid, methanol, room temperature. Acompound of formula III can be reacted with2-(2,6-dioxo-3-piperidyl)-5-hydroxy-isoindoline-1,3-dione to providecompounds of formula IV using suitable reaction conditions for analkylation reaction, e.g. diisopropylethylamine, potassium iodide, DMSOor acetonitrile, 80° C.

Exemplary Synthesis of Exemplary Compound 53N-(5-((4-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)ethoxy)ethoxy)ethyl)piperazin-1-yl)methyl)-1-phenyl-1H-benzo[d]imidazol-2-yl)-3-(trifluoromethyl)benzamide

Step 1:

To a solution of 4-fluoro-3-nitro-benzaldehyde (15 g, 88.7 mmol, 1 eq)and acetic acid (16.0 g, 266 mmol, 15.2 mL, 3 eq) in 1,2-dichloroethane(300 mL) was added a solution of tert-butyl piperazine-1-carboxylate(16.5 g, 88.7 mmol, 1 eq) in 1,2-dichloroethane (80 mL) at 0° C. over aperiod of 1 hour, followed by addition of sodium triacetoxyborohydride(75.2 g, 354 mmol, 4 eq) in portions. The mixture was stirred at 25° C.for 12 hours. LCMS analysis showed formation of the desired compound.The reaction mixture was quenched by addition of a 1M solution ofhydrochloric acid to adjust the pH to be 5. The pH was then adjusted to8 with the addition of an aqueous solution of sodium bicarbonate. Themixture was then extracted with ethyl acetate (300 mL×3). The combinedorganic phase was dried over sodium sulfate, filtered and concentratedunder reduced pressure. The resulting residue was purified by silica gelcolumn chromatography (petroleum ether/ethyl acetate=5/1 to 1/1) toafford tert-butyl4-[(4-fluoro-3-nitro-phenyl)methyl]piperazine-1-carboxylate (24 g, 80%yield) as a yellow solid. MS (ESI) m/z: 340.1 [M+H]⁺.

Step 2:

A mixture of tert-butyl4-[(4-fluoro-3-nitro-phenyl)methyl]piperazine-1-carboxylate (10 g, 29.5mmol, 1 eq), aniline (11.0 g, 118 mmol, 10.8 mL, 4 eq),N,N-diisopropylethylamine (7.62 g, 58.9 mmol, 10.3 mL, 2 eq) indimethylsulfoxide (10 mL) was degassed and purged with nitrogen 3 times.The reaction mixture was allowed to stir at 130° C. for 12 hours under anitrogen atmosphere. The reaction mixture was concentrated to give aresidue. To the residue was added water (200 mL) and the mixture wasextracted with ethyl acetate (200 mL×3). The combined organic phase waswashed with brine (50 mL), dried over anhydrous sodium sulfate,filtered, and concentrated in vacuo. The residue was purified by silicagel column chromatography (petroleum ether/ethyl acetate=3/1 to 1/1), toafford tert-butyl4-[(4-anilino-3-nitro-phenyl)methyl]piperazine-1-carboxylate (10 g, 82%yield) as a brown oil. MS (ESI) m/z: 413.1 [M+H]⁺.

Step 3:

A mixture of tert-butyl4-[(4-anilino-3-nitro-phenyl)methyl]piperazine-1-carboxylate (10 g, 24.2mmol, 1 eq), ammonium chloride (25.9 g, 485 mmol, 20 eq), zinc (32 g,489 mmol, 20.1 eq) in ethyl alcohol (150 mL) was degassed and purgedwith nitrogen 3 times. The reaction mixture was then heated to 50° C.and allowed to stir for 12 hours under a nitrogen atmosphere. LCMSanalysis showed formation of the desired compound. The reaction wasfiltered and the filtrate was concentrated in vacuo to give the crudeproduct. The residue was purified by silica gel column chromatography(petroleum ether/ethyl acetate=3/1 to 0/1), to afford tert-butyl4-[(3-amino-4-anilino-phenyl)methyl]piperazine-1-carboxylate (9 g, 97%yield) as a brown oil. MS (ESI) m/z: 405.2 [M+Na]⁺.

Step 4:

To a solution of cyanogen bromide (3 g, 28.3 mmol, 1.20 eq) in ethylalcohol (80 mL) was added tert-butyl4-[(3-amino-4-anilino-phenyl)methyl]piperazine-1-carboxylate (9 g, 23.5mmol, 1 eq) in ethyl alcohol (50 mL) at 0° C. The reaction mixture wasstirred at 25° C. for 12 hours. LCMS showed desired compound wasdetected. The reaction mixture was concentrated and to the residue wasadded water (100 mL) and the mixture was extracted with ethyl acetate(100 mL×3). The combined organic phase was washed with brine (20 mL),dried over anhydrous sodium sulfate, filtered and concentrated in vacuo.The crude product was purified by preparative HPLC to yield tert-butyl4-[(2-amino-1-phenyl-benzimidazol-5-yl)methyl]piperazine-1-carboxylate(1.7 g, 18% yield) obtained as a brown solid. MS (ESI) m/z: 408.3[M+H]⁺.

Step 5:

To a solution of 3-(trifluoromethyl)benzoic acid (793 mg, 4.17 mmol, 1eq) and HATU (1.90 g, 5.01 mmol, 1.2 eq) in dimethylformamide (30 mL)was added N-ethyl-N-propan-2-ylpropan-2-amine (1.62 g, 12.5 mmol, 2.18mL, 3 eq). After stirring at 25° C. for 10 minutes, a solution oftert-butyl4-[(2-amino-1-phenyl-benzimidazol-5-yl)methyl]piperazine-1-carboxylate(1.7 g, 4.17 mmol, 1 eq) in dimethylformamide (20 mL) was added. Theresulting mixture was allowed to stir at 25° C. for 11 hours and 50minutes. LCMS analysis showed desired compound was detected. Thereaction mixture was concentrated to give a residue. To the reactionmixture was added water (50 mL) and the mixture was extracted with ethylacetate (50 mL×3). The combined organic phase was washed with brine (30mL), dried over anhydrous sodium sulfate, filtered and concentrated invacuo. The residue was purified by silica gel column chromatography(eluting with a gradient from 5 to 1:1 petroleum ether:ethyl acetate) toafford tert-butyl4-[[1-phenyl-2-[[3-(trifluoromethyl)benzoyl]amino]benzimidazol-5-yl]methyl]piperazine-1-carboxylate(2.3 g, 95% yield) as a brown solid. MS (ESI) m/z: 580.3 [M+H]⁺.

Step 6:

To a solution of tert-butyl4-[[1-phenyl-2-[[3-(trifluoromethyl)benzoyl]amino]benzimidazol-5-yl]methyl]piperazine-1-carboxylate(2.3 g, 3.97 mmol, 1 eq) in dioxane (10 mL) was added a solution ofhydrochloric acid in dioxane (4 M, 0.99 mL, 1 eq). The mixture wasstirred at 25° C. for 12 hours. LCMS analysis confirmed the reaction tobe complete. The reaction mixture was concentrated to provide crudeN-[1-phenyl-5-(piperazin-1-ylmethyl)benzimidazol-2-yl]-3-(trifluoromethyl)benzamide(1 g, crude), obtained as a brown solid used as is in subsequentreactions. MS (ESI) m/z: 480.1 [M+H]⁺.

Step 7:

To a solution ofN-[1-phenyl-5-(piperazin-1-ylmethyl)benzimidazol-2-yl]-3-(trifluoromethyl)benzamide(300 mg, 0.625 mol, 1 eq), 2-[2-(2-oxoethoxy)ethoxy]ethyl4-methylbenzenesulfonate, Intermediate 7 (283 mg, 0.938 mmol, 1.5 eq) inmethanol (5 mL) and acetic acid (0.5 mL) was added 2-methylpyridineborane complex (100 mg, 0.938 mmol, 1.5 eq). The mixture was stirred at25° C. for 12 hours. LCMS analysis showed the reaction was complete. Tothe reaction mixture was added water (50 mL) and the mixture wasextracted with ethyl acetate (50 mL×3). The combined organic phase waswashed with brine (20 mL), dried over anhydrous sodium sulfate,filtered, and concentrated in vacuo. The resulting residue was purifiedby silica gel column chromatography (dichloromethane/methyl alcohol=20/1to 5:1), to afford2-[2-[2-[4-[[1-phenyl-2-[[3-(trifluoromethyl)benzoyl]amino]benzimidazol-5-yl]methyl]piperazin-1-yl]ethoxy]ethoxy]ethyl4-methylbenzenesulfonate (200 mg, 42% yield) as a brown oil. MS (ESI)m/z: 766.3 [M+H]⁺.

Step 8:

To a mixture of2-[2-[2-[4-[[1-phenyl-2-[[3-(trifluoromethyl)benzoyl]amino]benzimidazol-5-yl]methyl]piperazin-1-yl]ethoxy]ethoxy]ethyl-4-methylbenzenesulfonate(0.1 g, 0.13 mmol, 1 eq) and2-(2,6-dioxo-3-piperidyl)-5-hydroxyisoindoline-1,3-dione (60 mg, 0.22mmol, 1.68 eq) in dimethylformamide (1.5 mL) was added potassiumcarbonate (80 mg, 0.579 mmol, 4.4 eq). The reaction mixture was stirredat 50° C. for 10 hours. TLC analysis indicated the reaction wascomplete. The mixture was poured into ice-water (10 mL). The aqueousphase was extracted with ethyl acetate (10 mL×3). The combined organicphase was washed with brine (10 mL), dried with anhydrous sodiumsulfate, filtered and concentrated under vacuum. The crude product waspurified by preparative HPLC to affordN-(5-((4-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)ethoxy)ethoxy)ethyl)piperazin-1-yl)methyl)-1-phenyl-1H-benzo[d]imidazol-2-yl)-3-(trifluoromethyl)benzamide(7.5 mg, 5% yield, 99% purity), obtained as an off-white solid. MS (ESI)m/z: 868.3 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 12.56-12.88 (m, 1H),9.63-9.98 (m, 1H), 8.51 (s, 1H), 8.39 (d, J=8.0 Hz, 1H), 7.84 (d, J=8.4Hz, 1H), 7.69 (d, J=7.6 Hz, 1H), 7.60-7.66 (m, 4H), 7.48-7.56 (m, 2H),7.44 (d, J=2.4 Hz, 1H), 7.28-7.32 (m, 2H), 7.19 (s, 2H), 5.05 (dd,J=12.4, 5.2 Hz, 1H), 4.29 (t, J=4.46 Hz, 2H), 3.94 (t, J=4.8 Hz, 2H),3.65-3.75 (m, 6H), 3.32-3.51 (m, 2H), 2.73-2.99 (m, 4H), 2.67 (s, 4H),2.46 (s, 4H), 2.00-2.35 (m, 2H).

The following compounds may be prepared in an analogous fashion as theexemplary synthesis described for Exemplary Compound 53.

Exemplary Compound [M + H]⁺

898.60 Exemplary Compound 54

Exemplary Compound 55N-(5-((4-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)ethyl)piperazin-1-yl)methyl)-1-phenyl-1H-benzo[d]imidazol-2-yl)-3-(trifluoromethyl)benzamide

To a mixture ofN-[1-phenyl-5-(piperazin-1-ylmethyl)benzimidazol-2-yl]-3-(trifluoromethyl)benzamide (Example 51 Intermediate) (0.15 g, 0.31 mmol, 1 eq) and2-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]oxyacetaldehyde,Intermediate 8 (202 mg, 0.64 mmol, 2.04 eq) in tetrahydrofuran (5 mL)was added acetic acid (10.6 mg, 0.18 mmol, 0.01 mL, 0.6 eq). The mixturewas stirred at 25° C. for 0.5 hour, followed by addition of sodiumtriacetoxyborohydride (138 mg, 0.65 mmol, 2.08 eq) to the mixture. Themixture was stirred at 25° C. for 9.5 hours. LCMS analysis confirmed thereaction to be complete. To the reaction mixture was added water (20 mL)and the mixture was extracted with ethyl acetate (30 mL×3). The combinedorganic phase was washed with brine (20 mL), dried over anhydrous sodiumsulfate, filtered and concentrated in vacuo. The crude product waspurified by preparative HPLC to affordN-(5-((4-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)ethyl)piperazin-1-yl)methyl)-1-phenyl-1H-benzo[d]imidazol-2-yl)-3-(trifluoromethyl)benzamide(82.6 mg, 38% yield, 92% purity) as a white solid. MS (ESI) m/z: 780.3[M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 12.64 (s, 1H), 9.20 (s, 1H), 8.49 (s,1H), 8.37 (d, J=8.0 Hz, 1H), 7.80 (d, J=8.4 Hz, 1H), 7.69 (d, J=8.8 Hz,1H), 7.62-7 .66 (m, 4H), 7.52-7.57 (m, 1H), 7.48-7.52 (m, 1H), 7.39-7.41(m, 2H), 7.21-7.24 (m, 3H), 4.99 (dd, J=12.4, 5.2 Hz, 1H), 4.26 (t,J=5.2 Hz, 2H), 3.62-3.71 (m, 1H), 3.48-3.59 (m, 1H), 2.82-2.92 (m, 4H),2.64 (d, J=7.2 Hz, 4H), 2.50 (s, 4H), 2.11-2.20 (m, 2H).

The following compounds may be prepared in an analogous fashion as theexemplary synthesis described for Exemplary Compound 55.

Exemplary Compound [M + H]⁺

810.40 Exemplary Compound 56

854.43 Exemplary Compound 57

A compound of formula I may be reacted with a reagent II (commerciallyavailable or readily prepared using standard reaction techniques knownto one skilled in the art) where Z is an appropriate leaving group (e.g.OMs, OTs, Cl, Br, etc.) under O— alkylation conditions to produce acompound of formula III, wherein L represents an optional linker orportion of a linker and X is CH₂ or C═O. Suitable reactions conditionsfor O-alkylation entail the use of a base, e.g. NaH or potassiumcarbonate in a solvent such as DMF at 60° C. Compounds of formula IIImay react with a compound of formula IV through N-alkylation where Y isan appropriate leaving group (e.g. OMs, OTs, Cl, etc.) or throughreductive amination where Y is an aldehyde to produce compound offormula V. When Y is a leaving group, suitable reaction conditions arethose for an alkylation reaction, e.g. diisopropylethylamine, potassiumiodide, DMSO or acetonitrile, 80° C. When Y is an aldehyde, suitablereaction conditions are those for a reductive amination reaction, e.g.sodium cyanoborohydride, methanol, dichloromethane, acetic acid, roomtemperature.

Exemplary Synthesis of Exemplary Compound 58N-(2-(1-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)ethoxy)ethyl)piperidin-4-yl)-6-methoxy-2H-indazol-5-yl)-6-(trifluoromethyl)picolinamide

Step 1:

To a solution of 2-fluoro-4-methoxy-benzaldehyde (3 g, 19.46 mmol, 1 eq)in sulfuric acid (15 mL) was added a solution of nitric acid (1.35 mL)in sulfuric acid (2 mL) at −20° C. The mixture was stirred at −20 to−10° C. for 1 hour. The reaction mixture was poured onto ice-water (500mL) where upon a precipitate formed. The solid was collected byfiltration and was washed with water 100 mL (50 mL×2), and dried to givecompound 2-fluoro-4-methoxy-5-nitro-benzaldehyde (3.2 g, 16.07 mmol,82.56% yield) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ: 10.22 (s,1H), 8.46 (d, J=8 Hz, 1H), 6.88 (d, J=11 Hz, 1H), 4.06 (s,3H).

Step 2:

To a solution of 2-fluoro-4-methoxy-5-nitro-benzaldehyde (0.5 g, 2.51mmol, 1 eq) in dimethylsulfoxide (4 mL) was added sodium azide (326.46mg, 5.02 mmol, 2 eq). The mixture was stirred at 25° C. for 0.5 hour.The reaction mixture was quenched by the addition of water (20 mL) at25° C., and then diluted with ethyl acetate (20 mL). The mixture wasextracted with ethyl acetate (20 mL×2). The combined organic layers werewashed with brine (50 mL×3), dried over anhydrous sodium sulfate,filtered and concentrated under reduced pressure to yield crude2-azido-4-methoxy-5-nitro-benzaldehyde (0.5 g, 2.25 mmol, 89.64% yield),obtained as a white solid. ¹H NMR (400 MHz, CDCl₃) δ: 10.2 (s, 1H), 8.46(s, 1H), 6.81 (s, 1H), 4.10 (s,3H).

Step 3:

To a solution of 2-azido-4-methoxy-5-nitro-benzaldehyde (0.5 g, 2.25mmol, 1 eq) in toluene (10 mL) was added tert-butyl4-aminopiperidine-1-carboxylate (450.76 mg, 2.25 mmol, 1 eq). Themixture was stirred at 120° C. for 1 hour. The reaction mixture wasconcentrated under reduced pressure to give a residue which was purifiedby silica gel chromatography to afford tert-butyl4-(6-methoxy-5-nitro-indazol-2-yl)piperidine-1-carboxylate (0.8 g, 2.13mmol, 94.4% yield) which was obtained as a white solid. ¹H NMR (400 MHz,CDCl₃) δ: 8.22 (s, 1H), 8.08 (s, 1H), 7.11 (s, 1H), 4.54 (m, 1H), 4.33(m, 2H), 3.97 (s,3H), 2.96 (m, 2H), 2.24 (m, 2H), 2.10 (m, 2H), 1.49 (s,9H).

Step 4:

To a solution of tert-butyl4-(6-methoxy-5-nitro-indazol-2-yl)piperidine-1-carboxylate (0.8 g, 2.13mmol, 1 eq) in ethanol (10 mL) was added Pd/C (0.5 g, 2.13 mmol, 10%purity, 1 eq) under hydrogen (15 psi). The mixture was stirred at 25° C.for 1 hour. The reaction mixture was concentrated under reduced pressureto give a residue which was purified by silica gel column chromatographyto afford tert-butyl4-(5-amino-6-methoxy-indazol-2-yl)piperidine-1-carboxylate (0.6 g, 1.73mmol, 81.49% yield), obtained as a white solid. ¹H NMR (400 MHz, CDCl₃)δ: 7.61 (s, 1H), 6.94 (s, 1H), 6.75 (s, 1H), 4.45 (m, 1H), 4.39 (m, 2H),3.91 (s,3H), 2.91 (m, 2H), 2.20 (m, 2H), 2.05 (m, 2H), 1.48 (s, 9H).

Step 5:

To a solution of 6-(trifluoromethyl)pyridine-2-carboxylic acid (198.60mg, 1.04 mmol, 1.2 eq) in N,N-dimethylformamide (5 mL) was added HATU(395.1 mg, 1.04 mmol, 1.2 eq), N,N-diisopropylethylamine (335.77 mg,2.60 mmol, 452.52 μL, 3 eq) and tert-butyl4-(5-amino-6-methoxy-indazol-2-yl)piperidine-1-carboxylate (0.3 g, 866μmol, 1 eq). The mixture was stirred at 25° C. for 0.5 hour. Thereaction mixture was quenched by the addition of water (20 mL) at 25°C., and then diluted with ethyl acetate (50 mL). The mixture was thenextracted with ethyl acetate (50 mL×2). The combined organic layers werewashed with brine (50 mL×3), dried over anhydrous sodium sulfate,filtered and concentrated under reduced pressure to give a residue. Theresidue was purified by silica gel column chromatography to yieldtert-butyl4-[6-methoxy-5-[[6-(trifluoromethyl)pyridine-2-carbonyl]amino]indazol-2-yl]piperidine-1-carboxylate(0.36 g, 693 μmol, 80.0% yield), obtained as a white solid. ¹H NMR (400MHz, CDCl₃) δ: 10.72 (s, 1H), 8.83 (s, 1H), 8.49 (d, J=10.4, 1H), 8.12(t, J=10.4, 1H), 7.80 (s, 1H), 7.80 (d, J=10.4, 1H), 7.06 (s, 1H), 4.48(m, 1H), 4.32 (m, 2H), 4.04 (s,3H), 2.96 (m, 2H), 2.20 (m, 2H), 2.10 (m,2H), 1.49 (s, 9H).

Step 6:

To a solution of tert-butyl4-[6-methoxy-5-[[6-(trifluoromethyl)pyridine-2-carbonyl]amino]indazol-2-yl]piperidine-1-carboxylate(0.36 g, 692.95 umol, 1 eq) in methanol (2 mL) was added 4 Mhydrochloric acid in dioxane (10 mL). The mixture was stirred at 25° C.for 1 hour. The reaction mixture was concentrated under reduced pressureto yieldN-[6-methoxy-2-(4-piperidyl)indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide(0.31 g, 680 mol, 98.1% yield, hydrochloric acid). MS (ESI) m/z: 420.2.[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ: 10.52 (s, 1H), 9.09 (m, 2H), 8.71(s, 1H), 8.38 (m, 3H), 8.24 (d, J=8.0, 1H), 7.19 (s, 1H), 4.78 (m, 1H),3.99 (s,3H), 3.46 (m, 2H), 3.13 (m, 2H), 2.28 (m, 4H).

Step 7:

To a mixture ofN-[6-methoxy-2-(4-piperidyl)indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide(150 mg, 0.36 mmol, 1 eq) and2-[2-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]oxyethoxy]acetaldehyde,Intermediate 9 (193 mg, 0.54 mmol, 1.5 eq) in tetrahydrofuran (15 mL)was added acetic acid (10.7 mg, 0.18 mmol, 0.01 mL, 0.5 eq). The mixturewas stirred at 25° C. for 0.5 hour, followed by addition of sodiumtriacetoxyborohydride (152 mg, 0.72 mmol, 2 eq) to the mixture. Themixture was stirred at 25° C. for 11.5 hours. LCMS analysis confirmedthe reaction to be complete and to the reaction mixture was added water(20 mL). The mixture was extracted with ethyl acetate (30 mL×3). Thecombined organic phase was washed with brine (20 mL), dried overanhydrous sodium sulfate, filtered and concentrated in vacuo. The crudeproduct was purified by preparative HPLC to yieldN-(2-(1-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)ethoxy)ethyl)piperidin-4-yl)-6-methoxy-2H-indazol-5-yl)-6-(trifluoromethyl)picolinamide(5.5 mg, 2% yield, 96% purity), obtained as a white solid. MS (ESI) m/z:764.3 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 10.72 (s, 1H), 8.86 (s, 1H),8.52 (d, J=8.0 Hz, 2H), 8.13 (t, J=8.0 Hz, 1H), 7.84-7 .90 (m, 2H), 7.80(d, J=8.4 Hz, 1H), 7.42 (d, J=2.4 Hz, 1H), 7.23-7.26 (m, 1H), 7.09 (s,1H), 4.98 (dd, J=12.4, 5.6 Hz, 1H), 4.42 (s, 1H), 4.25-4.35 (m, 2H),4.04 (s, 3H), 3.88-3.93 (m, 2H), 3.77 (s, 2H), 3.21 (s, 2H), 2.57-2.99(m, 6H), 2.12-2.32 (m, 6H).

The following compounds may be prepared in an analogous fashion as theexemplary synthesis described for Exemplary Compound 58.

Exemplary Compound [M + H]⁺

808.54 Exemplary Compound 59

A compound of formula I may be reacted with a reagent II (commerciallyavailable or readily prepared using standard reaction techniques knownto one skilled in the art) where Y is an appropriate leaving group (e.g.OMs, OTs, Cl, Br etc.) under etherification or alkylation conditions toproduce a compound of formula III, wherein L represents an optionallinker or portion of a linker. Suitable reaction conditions forO-alkylation entail use of an appropriate base e.g., potassium carbonatein acetonitrile or DMF at 60° C. Compounds of formula III may react witha compound of formula IV through N-alkylation where Y is an appropriateleaving group (e.g. OMs, OTs, Cl, Br etc.) to produce a compound offormula V. Suitable reaction conditions are those for an alkylationreaction, e.g. diisopropylethylamine, potassium iodide, DMSO oracetonitrile, 80° C. A compound of formula V can then undergo acyclization reaction to afford compounds of formula VI.

Exemplary Synthesis of Exemplary Compound 60N-(2-(1-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)ethoxy)ethyl)piperidin-4-yl)-6-methoxy-2H-indazol-5-yl)-6-(trifluoromethyl)picolinamide

Step 1:

To a solution of tert-butyl5-amino-4-(5-hydroxy-1-oxo-isoindolin-2-yl)-5-oxo-pentanoate (0.5 g,1.50 mmol, 1 eq) in acetonitrile (10 mL) was added potassium carbonate(268.67 mg, 1.94 mmol, 1.3 eq) and 1-bromo-2-(2-bromoethoxy)ethane(693.59 mg, 2.99 mmol, 374.9 μL, 2 eq). The mixture was stirred at 60°C. for 12 hours. The reaction mixture was concentrated to give a residuewhich was purified by silica gel column chromatography (petroleumether/ethyl acetate=1/1 to 0:1) to afford tert-butyl5-amino-4-[5-[2-(2-bromoethoxy)ethoxy]-1-oxo-isoindolin-2-yl]-5-oxo-pentanoate (0.53 g, 982.76 umol,66% yield, 90% purity) obtained as a yellow oil. MS (ESI) m/z: 487.0[M+H]⁺.

Step 2:

To a solution of tert-butyl5-amino-4-[5-[2-(2-bromoethoxy)ethoxy]-1-oxo-isoindolin-2-yl]-5-oxo-pentanoate(0.25 g, 515.07 umol, 1 eq) in acetonitrile (10 mL) was addedN-ethyl-N-isopropylpropan-2-amine (133.14 mg, 1.03 mmol, 179.4 uL, 2.0eq) andN-[6-methoxy-2-(4-piperidyl)indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide(Example 56 Intermediate) (216.0 mg, 515.1 μmol, 1 eq). The mixture wasstirred at 70° C. for 12 hours. The reaction mixture was concentrated togive a residue which was purified by silica gel column chromatography(petroleum ether/ethyl acetate=1/1 to 0:1) to yield tert-butyl5-amino-4-[5-[2-[2-[4-[6-methoxy-5-[[6-(trifluoromethyl)pyridine-2-carbonyl]amino]indazol-2-yl]-1-piperidyl]ethoxy]ethoxy]-1-oxo-isoindolin-2-yl]-5-oxo-pentanoate(0.4 g, 466.1 μmol, 90% yield, 96% purity), obtained as a white solid.MS (ESI) m/z: 823.86 [M+H]⁺.

Step 3:

To a solution of tert-butyl5-amino-4-[5-[2-[2-[4-[6-methoxy-5-[[6-(trifluoromethyl)pyridine-2-carbonyl]amino]indazol-2-yl]-1-piperidyl]ethoxy]ethoxy]-1-oxo-isoindolin-2-yl]-5-oxo-pentanoate(0.15 g, 182.07 μmol, 1 eq) in acetonitrile (5 mL) was addedbenzenesulfonic acid (86.4 mg, 546.2 μmol, 3 eq). The mixture wasstirred at 80° C. for 20 hours. The reaction mixture was concentrated togive a residue which was purified by preparative HPLC to affordN-(2-(1-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)ethoxy)ethyl)piperidin-4-yl)-6-methoxy-2H-indazol-5-yl)-6-(trifluoromethyl)picolinamide(48.8 mg, 63.14 μmol, 35% yield, 97% purity), obtained as a white solid.MS (ESI) m/z: 748.4 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.98 (s,1H) 10.51 (s, 1H) 8.69 (s, 1H) 8.33-8.52 (m, 3H) 8.23 (d, J=7.70 Hz, 1H)7.64 (d, J=8.30 Hz, 1H) 7.15-7.24 (m, 2H) 7.08 (dd, J=8.38, 2.14 Hz, 1H)5.08 (dd, J=13.34, 5.01 Hz, 1H) 4.18-4.43 (m, 5H) 3.99 (s, 3H) 3.74-3.85(m, 2H) 3.63 (t, J=5.76 Hz, 2H) 2.83-3.12 (m, 3H) 2.57 (br t, J=5.82 Hz,3H) 2.30-2.44 (m, 2H) 1.90-2.26 (m, 7H).

The following compounds may be prepared in an analogous fashion as theexemplary synthesis described for Exemplary Compound 60.

Exemplary Compound [M + H]⁺

794.56 Exemplary Compound 61

Examples

Biochemical Assay for IRAK4 Kinase Inhibition.

A Z′-Lyte assay based on a fluorescence resonance energy transfer (FRET)readout was developed for measuring IRAK4-dependent phosphorylation of aFRET-peptide substrate as described by Thermo Fisher Scientific (GrandIsland, N.Y.). At a starting concentration of 1.5 mM, the identifiedcompounds were serially diluted with 100% dimethyl sulfoxide (DMSO) in3-fold increments, into Greiner bio-one 96-well plates (cat. #: 650201,Greiner bio-one, Monroe, N.C.). Compounds were then transferred tointermediate Greiner bio-one 96-well plates and diluted 10-fold withKinase assay buffer (25 mM HEPES, pH 7.5, 10 mM MgCl₂, 10 mM MnCl₂, 1 mMEGTA, and 0.01% Brij-35, 2 mM DTT). Three μL of the serially dilutedcompounds were then transferred in duplicate to low-volume 384-wellblack proxiplates (cat. #: 6008269; Perkin Elmer, Akron, Ohio), to giveduplicate twelve-point concentration curves. Six μl of a 2.5× solutionof IRAK4 enzyme (cat #: 40064, BPS Bioscience, San Diego, Calif.) inkinase buffer was added to each well, followed by a 10 minutespre-incubation step. Reactions were initiated by adding 6 μl of a 2.5×substrate mix of ATP and Z′-Lyte Ser/Thr 7 peptide (cat. #: PV3180,Thermo Fisher Scientific, Grand Island, N.Y.) and proceeded at roomtemperature for 1 hour. The final concentration of key reagents in the15 uL kinase reactions were 2 μM substrate, 2 nM enzyme, and 1 mM ATP,with dose responses starting at 30 μM compound. At the end of the kinasereactions, 5 μl of developing solution (as instructed in for cat. #:PV3180, Thermo Fisher Scientific, Grand Island, N.Y.) was added to eachwell and incubated at room temperature for 1 hour. All wells were readon an Envision 2105 Multilabel fluorescence plate reader (Perkin Elmer,Waltham, Mass.) at 400 nm excitation and 460 nm/530 nm emission. Plusand minus 100% inhibition controls were used to calculate percentinhibition and IC50 curves were generated using Graphpad Prism (LaJolla, Calif.).

Western Blot Assay for Assessing Degradation of IRAK4.

MCF7 cells, purchased from ATCC (Manassas, Va.), were used at a passagerange of 2-19. Cells were seeded at 50% confluency in 96-well plates at180 l/well in cell media (Dulbecco's Modified Eagle medium/nutrient F-12Ham-10% Fetal Bovine Serum) and incubated overnight. The next morning,compounds were serially diluted and added (20 μl into 180 μl media) at afinal DMSO concentration of 0.1%. Cells were rinsed with cell media andreplaced with compounds in media, followed by incubation overnight.After a 24 hour incubation with compound, cell were harvested (90-100%confluent at harvest). Cells were then washed once with 100 μl ofDulbecco's hosphate-buffered saline and then lysed with 40 μl of lysisbuffer (IX RIPA+HALT protease inhibitor+HALT phosphatase inhibitor) onice for 10 minutes. Lysates were then cleaned by filtration in 1.2 μmfilter plates followed by western blotting. For each sample, 30 μl oflysate were added to 10 μl of 4×LDS sample buffer, then denatured at 95°C. for 5 minutes in the thermal cycler and placed on ice. Fifteen L ofeach sample were then loaded on 4-15% Tris/Glycine gels and run for 25minutes at 250 (constant) volts in 1×Tris/Glycine buffer. Protein wastransferred from gels to nitrocellulose using a BioRad Turbodry-transfer unit with the Turbo/midi default program. All blots wererinsed with ddH₂O and blocked for 1 hour at room temperature in 5%bovine serum albumin (BSA) in tris-buffered saline-Tween 20 (TBS-T)(0.1%) on rocker. Blots were exposed to primary antibody in 5% BSA inTBS-T (0.1%) overnight at 4° C. on rocker. Primary antibodies, diluted1:1000 in cell media, were as follows: anti-IRAK4 (cat.#: ab119942,Abcam, Cambridge, Mass.), anti-IRAK1 (cat. #: CST 4504S, Cell SignalingTechnology, Danvers, Mass.), and anti-Beta-actin (Cat. #: ab8227, Abcam,Cambridge, Mass.). Blots were then washed with TBS-T (0.1%) three timesfor 5 minutes on a rocker at room temperature. Secondary antibody(1:18,000 anti-rabbit-HRP and/or anti-mouse-HRP in 5% BSA in TBST (0.1%)was then added, and blots incubated at room temperature rocker for 1hour. Blots were washed 3 times in TBS-T (0.1%) for 5 minutes at roomtemperature on the rocker. Signal was developed with Femto Max substratefor 5 minutes and blots read on a ChemiDoc. Percent degradation wasassessed by comparing IRAK4 signal in compound vs. DMSO treated lysates.

IRAK4 and IRAK1 protein degradation by Example 2 and Example 3 wasexamined and illustrated in the blots of FIGS. 2B and 3B, respectively.The percent degradation of IRAK 4 by Example 2 and Example 3 are shownin FIGS. 2C and 3C (percent remaining is shown). Graphs of percentdegradation of IRAK1 by Examples 2 and 3 is not provided as nosignificant degradation was observed, as is demonstrated in the blots ofFIGS. 2B and 3B, respectively. Example 2 demonstrated a Dmax of 71% anda DC50 of 9.7 nM. Example 3 demonstrate a Dmax of 80% and a DC50 of 23nM.

IRAK 4 protein degradation by Example 60 was examined and is illustratedin the blots of FIG. 4B with vinculin as a loading control. The percentof IRAK4 degradation by Example 60 is shown in FIG. 4C (percentremaining is shown). Example 60 demonstrated a Dmax of 73% and a DC50 of3.5 nM.

Enzyme-Linked Immunosorbent Assay (ELISA) Assay for IRAK4 Degradation.

MCF7 cells, purchased from ATCC (Manassas, Va.), were used at a passagerange of 2-19. Cells were prepared and treated with compounds for 24hours, exactly as described above for the Western blots. The ELISA assaywas performed using the kit and instructions described by Abcam (cat. #:ab213472, Abcam Biotechnology, Cambridge, Mass.). Table 1 below providesand compares the ELISA IRAK4 degradation data to the western blot IRAK 4degradation data for Examples 2, 3, 4, and 5. Furthermore, FIG. 5 is agraph illustrating the ELISA IRAK4 degradation data.

TABLE 1 IRAK4 and IRAK 1 protein degradation by Examples 2-5. IRAK4 bywestern IRAK4 by ELISA DC50 % degraded DC50 % degraded Example 2 10 7115 76 Example 3 23 80 15 86 Example 4 25 87 25 89 Example 5 40 76 29 80

As shown in Table 1, as well as FIGS. 2C and 5, the western blot andELISA provided similar data for Examples 2-5.

Cell Proliferation Assay Using CellTiter-Glo.

Cells were lifted, washed and counted. White, clear-bottom 96-wellplates were seeded with 180 μl growth media per well. To allowsub-confluent growth for 3-5 days, seeding densities were as follows:OCI-Ly3 (from DSMZ, Braunschweig, Germany)=10000 cells/well; OCI-Ly19(from DSMZ, Braunschweig, Germany)=2000 cells/well; DHL-6 (from ATCC,Manassas, Va.)=2000 cells/well; MCF-7 (from ATCC, Manassas, Va.)=2000cells/well. One extra plate was seeded for a “time zero” CellTiter-Gloreading. Cells were allowed to adhere/incubate overnight at 37° C./5%CO₂. The next day, cells were treated in technical duplicate with 20 μlof 10× compound (1% DMSO) was added as appropriate. Plates were returnedto incubator for 3 or 5 days. The “time zero” plate was spun down at300×g, media flicked out and replaced with 100 μl fresh media and 100 μlCellTiter-Glo 2.0 (Promega, Madison, Wis.; plate was then read onEnvision 2105 with luminescence setting. At the end point (3 or 5 days),the compound treated plates were spun down at 300×g for 5 minutes, mediaflicked out, then replaced with 100 μl fresh media and 100 μlCellTiter-Glo 2.0. Plates were then read on the Envision with theluminescence setting.

TABLE 4 Exemplary compounds of the present disclosure Ex # StructureChemical Name 1

N-(5-((4-(2-((2- (2,6- dioxopiperidin-3- yl)-1,3- dioxoisoindolin-5-yl)oxy)ethyl)piper- azin-1-yl)methyl)- 1-((1s,4s)-4- (hydroxymeth-yl)cyclohexyl)- 1H- benzo[d]imidazol- 2-yl)-3-(trifluoro-methyl)benzamide C₄₂H₄₄F₃N₇O₇ 2

N-(5-((4-(2-(2-((2- (2,6- dioxopiperidin-3- yl)-1,3- dioxoisoindolin-5-yl)oxy)ethoxy)eth- yl)piperazin-1- yl)methyl)-1- ((1s,4s)-4-(hydroxymeth- yl)cyclohexyl)- 1H- benzo[d]imidazol- 2-yl)-3-(trifluoro-methyl)benzamide C₄₄H₄₈F₃N₇O₈ 3

N-(5-((4-(2-(2-(2- ((2-(2,6- dioxopiperidin-3- yl)-1,3-dioxoisoindolin-5- yl)oxy)ethoxy)eth- oxy)ethyl)piper-azin-1-yl)methyl)- 1-((1s,4s)-4- (hydroxymeth- yl)cyclohexyl)-1H-benzo[d]imidazol- 2-yl)-3-(trifluoro- methyl)benzamide C₄₆H₅₂F₃N₇O₉ 4

N-(5-((4-(2-(2-(2- (2-((2-(2,6- dioxopiperidin-3- yl)-1,3-dioxoisoindolin-5- yl)oxy)ethoxy)eth- oxy)ethoxy)eth- yl)piperazin-1-yl)methyl)-1- ((1s,4s)-4- (hydroxymeth- yl)cyclohexyl)-1H-benzo[d]imidazol- 2-yl)-3-(trifluoro- methyl)benzamide C₄₈H₅₆F₃N₇O₁₀ 5

N-(5-((4-(14-((2- (2,6- dioxopiperidin-3- yl)-1,3- dioxoisoindolin-5-yl)oxy)-3,6,9,12- tetraoxatetradec- yl)piperazin-1- yl)methyl)-1-((1s,4s)-4- (hydroxymeth- yl)cyclohexyl)-1H- benzo[d]imidazol-2-yl)-3-(trifluoro- methyl)benzamide C₅₀H₆₀F₃N₇O₁₁ 6

N-(5-((4-(2-(2-((2- (2,6- dioxopiperidin-3- yl)-1- oxoisoindolin-5-yl)oxy)ethoxy)eth- yl)piperazin-1- yl)methyl)-1- ((1s,4s)-4-(hydroxymeth- yl)cyclohexyl)-1H- benzo[d]imidazol- 2-yl)-3-(trifluoro-methyl)benzamide C₄₄H₅₀F₃N₇O₇ 7

N-(5-((4-(2-(2-((2- (2,6- dioxopiperidin-3- yl)-1,3- dioxoisoindolin-5-yl)oxy)ethoxy)eth- yl)piperazin-1- yl)methyl)-1- ((1s,4s)-4-methylcyclohexyl)- 1H- benzo[d]imidazol- 2-yl)-3-(trifluoro-methyl)benzamide C₄₄H₄₈F₃N₇O₇ 8

N-(5-((4-(2-(2-((2- (2,6- dioxopiperidin-3- yl)-1,3- dioxoisoindolin-5-yl)oxy)ethoxy)eth- yl)piperazin-1- yl)methyl)-1- ((1r,4r)-4-methylcyclohexyl)- 1H- benzo[d]imidazol- 2-yl)-3-(trifluoro-methyl)benzamide C₄₄H₄₈F₃N₇O₇ 9

N-(5-((4-((1-(2- (2,6- dioxopiperidin-3- yl)-1,3- dioxoisoindolin-5-yl)piperidin-4- yl)methyl)piper- azin-1-yl)methyl)- 1-((1s,4s)-4-(hydroxymeth- yl)cyclohexyl)-1H- benzo[d]imidazol- 2-yl)-3-(trifluoro-methyl)benzamide C₄₆H₅₁F₃N₈O₆ 10

N-(5-((4-((1-(2- ((2-(2,6- dioxopiperidin-3- yl)-1,3- dioxoisoindolin-5-yl)oxy)ethyl)piper- idin-4- yl)methyl)piper- azin-1-yl)methyl)-1-((1s,4s)-4- (hydroxymeth- yl)cyclohexyl)-1H- benzo[d]imidazol-2-yl)-3-(trifluoro- methyl)benzamide C₄₈H₅₅F₃N₈O₇ 11

(2S,4R)-4- hydroxy-1-((S)- 2-(2-(2-(4-((1- ((1SR,4SR)-4- (hydroxymeth-yl)cyclohexyl)-2- (3-(trifluorometh- yl)benzamido)-1H- benzo[d]imidazol-5-yl)methyl)piper- azin-1- yl)ethoxy)acet- amido)-3,3- dimethyl-butanoyl)-N-(4- (4-methylthiazol- 5-yl)benzyl)pyr- rolidine-2-carboxamide C₅₃H₆₆F₃N₉O₇S 12

(2S,4R)-4- hydroxy-1-((S)- 2-(2-(2-(2-(4- ((1-((1SR,4SR)-4-(hydroxymeth- yl)cyclohexyl)-2- (3-(trifluoro- methyl)benz- amido)-1H-benzo[d]imidazol- 5-yl)methyl)pi- perazin-1-yl)eth- oxy)ethoxy)acet-amido)-3,3- dimethyl- butanoyl)-N-(4- (4-methylthiazol- 5-yl)benzyl)pyr-rolidine-2- carboxamide C₅₅H₇₀F₃N₉O₈S 13

(2S,4R)-1-((S)-2- (tert-butyl)-14-(4- ((1-((1SR,4SR)-4- (hydroxymeth-yl)cyclohexyl)-2- (3-(trifluorometh- yl)benzamido)-1H- benzo[d]imidazol-5-yl)methyl)pi- perazin-1-yl)-4- oxo-6,9,12-trioxa- 3-azatetradecanoyl)- 4-hydroxy-N-(4- (4-methylthiazol- 5-yl)benzyl)pyr-rolidine-2- carboxamide C₅₇H₇₄F₃N₉O₉S 14

(2S,4R)-1-((S)-2- (tert-butyl)-17-(4- ((1-((1SR,4SR)-4- (hydroxymeth-yl)cyclohexyl)-2- (3-(trifluorometh- yl)benzamido)-1H- benzo[d]imidazol-5-yl)methyl)piper- azin-1-yl)-4-oxo- 6,9,12,15-tetraoxa- 3-azaheptadecanoyl)- 4-hydroxy-N-(4- (4-methylthiazol- 5-yl)benzyl)pyr-rolidine-2- carboxamide C₅₉H₇₈F₃N₉O₁₀S 25

N-(3-(4-(2-(2-(2- ((2-(2,6- dioxopiperidin- 3-yl)-1,3-dioxoisoindolin-5- yl)oxy)ethoxy)eth- oxy)ethyl)piper- azin-1-yl)-1-(5-methylpyridin- 2-yl)-1H-pyrazol- 5-yl)pyrazolo[1,5- a]pyrimidine-3-carboxamide C₃₉H₄₁N₁₁O₈ 26

N-(3-(4-(2-(2-(2- (2-((2-(2,6- dioxopiperidin-3- yl)-1,3-dioxoisoindolin-5- yl)oxy)ethoxy)eth- oxy)ethoxy)eth-yl)piperazin-1-yl)- 1-(5- methylpyridin-2- yl)-1H-pyrazol-5-yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide C₄₁H₄₅N₁₁O₉ 27

N-(3-(4-((S)-13- ((2S,4R)-4- hydroxy-2-((4-(4- methylthiazol- 5-yl)benzyl)carbamo- yl)pyrrolidine-1- carbonyl)-14,14- dimethyl-11-oxo-3,6,9-trioxa-12- azapentadecyl)pi- perazin-1-yl)-1- (5-methylpyridin-2-yl)-1H-pyrazol- 5-yl)pyrazolo[1,5- a]pyrimidine-3- carboxamideC₅₀H₆₃N₁₃O₈S 28

N-(3-(4-((S)-16- ((2S,4R)-4- hydroxy-2-((4-(4- methylthiazol-5-yl)benzyl)carbamo- yl)pyrrolidine-1- carbonyl)-17,17- dimethyl-14-oxo-3,6,9,12-tetraoxa- 15-azaoctadecyl)pi- perazin-1-yl)-1-(5-methylpyridin-2- yl)-1H-pyrazol-5- yl)pyrazolo[1,5- a]pyrimidine-3-carboxamide C₅₂H₆₇N₁₃O₉S 29

4-(((1r,4r)-4-(4-(2- ((2-(2,6- dioxopiperidin-3- yl)-1,3-dioxoisoindolin-5- yl)oxy)ethyl)piper- azin-1-yl)cyclohex-yl)amino)quinazo- line-6-carbonitrile 30

4-(((1r,4r)-4-(4-(2- (2-((2-(2,6- dioxopiperidin-3- yl)-1,3-dioxoisoindolin-5- yl)oxy)ethoxy)eth- yl)piperazin-1- yl)cyclohexyl)ami-no)quinazoline- 6-carbonitrile C₃₆H₄₀N₈O₆ 31

4-(((1r,4r)-4-(4-(2- (2-(2-((2-(2,6- dioxopiperidin-3- yl)-1,3-dioxoisoindolin-5- yl)oxy)ethoxy)eth- yl)piperazin-1- yl)cyclohexyl)ami-no)quinazoline- 6-carbonitrile C₃₈H₄₄N₈O₇ 32

4-(((1r,4r)-4-(4- (2-(2-(2-(2-((2- (2,6- dioxopiperidin- 3-yl)-1,3-dioxoisoindolin-5- yl)oxy)ethoxy)eth- oxy)ethoxy)eth- yl)piperazin-1-yl)cyclohexyl)ami- no)quinazoline- 6-carbonitrile C₄₀H₄₈N₈O₈ 33

4-(((1r,4r)-4-(4- (14-((2-(2,6- dioxopiperidin-3- yl)-1,3-dioxoisoindolin- 5-yl)oxy)-3,6,9,12- tetraoxatetradec- yl)piperazin-1-yl)cyclohexyl)ami- no)quinazoline- 6-carbonitrile C₄₂H₅₂N₈O₉ 34

4-(((1r,4r)-4-(4- ((2-(2-((2-(2,6- dioxopiperidin-3- yl)-1,3-dioxoisoindolin-5- yl)oxy)ethoxy)eth- yl)sulfonyl)piper- azin-1-yl)cyclohexyl)ami- no)quinazoline-6- carbonitrile C₃₆H₄₀N₈O₈S 35

4-(((1s,4s)-4-(4- ((2-(2-((2-(2,6- dioxopiperidin-3- yl)-1,3-dioxoisoindolin-5- yl)oxy)ethoxy)eth- yl)sulfonyl)piper- azin-1-yl)cyclohexyl)ami- no)quinazoline-6- carbonitrile C₃₆H₄₀N₈O₈S 36

4-(((1r,4r)-4-(4- ((2-(2-(2-((2-(2,6- dioxopiperidin-3- yl)-1,3-dioxoisoindolin-5- yl)oxy)ethoxy)eth- oxy)ethyl)sulfon- yl)piperazin-1-yl)cyclohexyl)ami- no)quinazoline- 6-carbonitrile C₃₈H₄₄N₈O₉S 37

4-(((1s,4s)-4-(4- ((2-(2-(2-((2-(2,6- dioxopiperidin-3- yl)-1,3-dioxoisoindolin-5- yl)oxy)ethoxy)eth- oxy)ethyl)sulfon- yl)piperazin-1-yl)cyclohexyl)ami- no)quinazoline-6- carbonitrile C₃₈H₄₄N₈O₉S 38

4-(((1r,4r)-4-(4- ((2-(2-(2-(2-((2- (2,6- dioxopiperidin-3- yl)-1,3-dioxoisoindolin-5- yl)oxy)ethoxy)eth- oxy)ethoxy)eth- yl)sulfonyl)piper-azin-1- yl)cyclohexyl)ami- no)quinazoline-6- carbonitrile C₄₀H₄₈N₈O₁₀S39

4-(((1s,4s)-4-(4- ((2-(2-(2-(2-((2- (2,6- dioxopiperidin-3- yl)-1,3-dioxoisoindolin-5- yl)oxy)ethoxy)eth- oxy)ethoxy)eth- yl)sulfonyl)piper-azin-1- yl)cyclohexyl)ami- no)quinazoline-6- carbonitrile C₄₀H₄₈N₈O₁₀S40

4-(((1r,4r)-4-(4- ((14-((2-(2,6- dioxopiperidin-3- yl)-1,3-dioxoisoindolin- 5-yl)oxy)-3,6,9,12- tetraoxatetradec-yl)sulfonyl)piper- azin-1- yl)cyclohexyl)ami- no)quinazoline-6-carbonitrile C₄₂H₅₂N₈O₁₁S 41

4-(((1s,4s)-4-(4- ((14-((2-(2,6- dioxopiperidin-3- yl)-1,3-dioxoisoindolin- 5-yl)oxy)-3,6,9,12- tetraoxatetradec-yl)sulfonyl)piper- azin-1- yl)cyclohexyl)ami- no)quinazoline-6-carbonitrile C₄₂H₅₂N₈O₁₁S 42

N-(1-((1s,4s)-4- (13-((2-(2,6- dioxopiperidin-3- yl)-1,3-dioxoisoindolin- 5-yl)oxy)-2,5,8,11- tetraoxatridec- yl)cyclohexyl)-5-(piperidin-1- ylmethyl)-1H- benzo[d]imidazol- 2-yl)-3-(trifluoro-methyl)benzamide C₄₉H₅₇F₃N₆O₁₀ 43

N-(1-((1s,4s)-4- ((2-(2-(2-((2-(2,6- dioxopiperidin-3- yl)-1,3-dioxoisoindolin-5- yl)oxy)ethoxy)eth- oxy)ethoxy)meth- yl)cyclohexyl)-5-(piperidin-1- ylmethyl)-1H- benzo[d]imidazol- 2-yl)-3- (trifluorometh-yl)benzamide C₄₇H₅₃F₃N₆O₉ 44

N-(1-((1s,4s)-4- ((2-(2-((2-(2,6- dioxopiperidin-3- yl)-1,3-dioxoisoindolin-5- yl)oxy)ethoxy)eth- oxy)methyl)cyclo- hexyl)-5-(piperidin-1- ylmethyl)-1H- benzo[d]imidazol- 2-yl)-3-(trifluoro-methyl)benzamide C₄₅H₄₉F₃N₆O₈ 45

N-(1-((1s,4s)-4- ((2-((2-(2,6- dioxopiperidin-3- yl)-1,3-dioxoisoindolin-5- yl)oxy)eth- oxy)methyl)cyclo- hexyl)-5-fluoro- 1H-benzo[d]imidazol- 2-yl)-3-(trifluoro- methyl)benzamide C₃₇H₃₃F₄N₅O₇ 46

N-(1-((1s,4s)-4- ((2-(2-((2-(2,6- dioxopiperidin-3- yl)-1,3-dioxoisoindolin-5- yl)oxy)ethoxy)eth- oxy)methyl)cyclo- hexyl)-5-fluoro-1H- benzo[d]imidazol- 2-yl)-3-(trifluoro- methyl)benzamide C₃₉H₃₇F₄N₅O₈47

N-(1-((1s,4s)-4- ((2-(2-(2-((2-(2,6- dioxopiperidin-3- yl)-1,3-dioxoisoindolin-5- yl)oxy)ethoxy)eth- oxy)ethoxy)meth- yl)cyclohexyl)-5-fluoro-1H- benzo[d]imidazol- 2-yl)-3-(trifluoro- methyl)benzamideC₄₁H₄₁F₄N₅O₉ 48

N-(1-((1s,4s)-4- (13-((2-(2,6- dioxopiperidin-3- yl)-1,3-dioxoisoindolin-5- yl)oxy)-2,5,8,11- tetraoxatridec- yl)cyclohexyl)-5-fluoro-1H- benzo[d]imidazol- 2-yl)-3-(trifluoro- methyl)benzamideC₄₃H₄₅F₄N₅O₁₀ 49

N-(1-(3-((2-(2-(2- ((2-(2,6- dioxopiperidin- 3-yl)-1,3-dioxoisoindolin-5- yl)oxy)ethoxy)eth- oxy)ethyl)(meth- yl)amino)phenyl)-5-fluoro-1H- benzo[d]imidazol- 2-yl)-3-(trifluoro- methyl)benzamideC₄₁H₃₆F₄N₆O₈ 50

N-(1-(3-((2-((2- (2,6- dioxopiperidin-3- yl)-1,3- dioxoisoindolin-5-yl)oxy)eth- yl)(methyl)ami- no)phenyl)-5- fluoro-1H- benzo[d]imidazol-2-yl)-3-(trifluoro- methyl)benzamide C₃₇H₂₈F₄N₆O₆ 51

N-(1-(3-((2-(2-((2- (2,6- dioxopiperidin- 3-yl)-1,3- dioxoisoindolin-5-yl)oxy)ethoxy)eth- yl)(methyl)amin- o)phenyl)-5-fluoro- 1H-benzo[d]imidazol- 2-yl)-3-(trifluoro- methyl)benzamide C₃₉H₃₂F₄N₆O₇ 52

N-(1-(3-((2-(2-(2- (2-((2-(2,6- dioxopiperidin-3- yl)-1,3-dioxoisoindolin-5- yl)oxy)ethoxy)eth- oxy)ethoxy)eth- yl)(methyl)amin-o)phenyl)-5- fluoro-1H- benzo[d]imidazol- 2-yl)-3-(trifluoro-methyl)benzamide C₄₃H₄₀F₄N₆O₉ 53

N-(5-((4-(2-(2- (2-((2-(2,6- dioxopiperidin- 3-yl)-1,3-dioxoisoindolin-5- yl)oxy)ethoxy)eth- oxy)ethyl)piper-azin-1-yl)methyl)- 1-phenyl-1H- benzo[d]imidazol- 2-yl)-3-(trifluoro-methyl)benzamide C₄₅H₄₄F₃N₇O₈ 54

N-(5-((4-(2-(2-(2- ((2-(2,6- dioxopiperidin- 3-yl)-1,3-dioxoisoindolin-5- yl)oxy)ethoxy)eth- oxy)ethyl)piper-azin-1-yl)methyl)- 1-(3- methoxyphenyl)- 1H- benzo[d]imidazol-2-yl)-3-(trifluoro- methyl)benzamide C₄₆H₄₆F₃N₇O₉ 55

N-(5-((4-(2-((2- (2,6- dioxopiperidin-3- yl)-1,3- dioxoisoindolin-5-yl)oxy)ethyl)piper- azin-1-yl)methyl)- 1-phenyl-1H- benzo[d]imidazol-2-yl)-3-(trifluoro- methyl)benzamide C₄₁H₃₆F₃N₇O₆ 56

N-(5-((4-(2-((2- (2,6- dioxopiperidin-3- yl)-1,3- dioxoisoindolin-5-yl)oxy)ethyl)piper- azin-1-yl)methyl)- 1-(3- methoxyphenyl)- 1H-benzo[d]imidazol- 2-yl)-3-(trifluoro- methyl)benzamide C₄₂H₃₈F₃N₇O₇ 57

N-(5-((4-(2-(2-((2- (2,6- dioxopiperidin- 3-yl)-1,3- dioxoisoindolin-5-yl)oxy)ethoxy)eth- yl)piperazin-1- yl)methyl)-1-(3- methoxyphenyl)- 1H-benzo[d]imidazol- 2-yl)-3-(trifluoro- methyl)benzamide C₄₄H₄₂F₃N₇O₈ 58

N-(2-(1-(2-(2-((2- (2,6- dioxopiperidin- 3-yl)-1,3- dioxoisoindolin-5-yl)oxy)ethoxy)eth- yl)piperidin-4-yl)- 6-methoxy-2H- indazol-5-yl)-6-(trifluorometh- yl)picolinamide C₃₇H₃₆F₃N₇O₈ 59

N-(2-(1-(2-(2-(2- ((2-(2,6- dioxopiperidin- 3-yl)-1,3-dioxoisoindolin-5- yl)oxy)ethoxy)eth- oxy)ethyl)piper- idin-4-yl)-6-methoxy-2H- indazol-5-yl)-6- (trifluorometh- yl)picolinamideC₃₉H₄₀F₃N₇O₉ 60

N-(2-(1-(2-(2-((2- (2,6- dioxopiperidin- 3-yl)-1- oxoisoindolin-5-yl)oxy)ethoxy)eth- yl)piperidin-4-yl)- 6-methoxy-2H- indazol-5-yl)-6-(trifluorometh- yl)picolinamide C₃₇H₃₈F₃N₇O₇ 61

N-(2-(1-(2-(2-(2- ((2-(2,6- dioxopiperidin- 3-yl)-1- oxoisoindolin-5-yl)oxy)ethoxy)eth- oxy)ethyl)piper- idin-4-yl)-6- methoxy-2H-indazol-5-yl)-6- (trifluorometh- yl)picolinamide C₃₉H₄₂F₃N₇O₈ 62

N-(2-(1-(2-(2-(2- ((2-(2,6- dioxopiperidin- 3-yl)-1,3-dioxoisoindolin-4- yl)amino)eth- oxy)ethoxy)eth- yl)piperidin-4-yl)-6-methoxy-2H- indazol-5-yl)-6- (trifluorometh- yl)picolinamideC₃₉H₄₁F₃N₈O₈ 63

N-(2-(1-((1-(2-((2- (2,6- dioxopiperidin-3- yl)-1,3- dioxoisoindolin-5-yl)oxy)ethyl)piper- idin- 4-yl)methyl)piper- idin-4-yl)- 6-methoxy-2H-indazol-5-yl)-6- (trifluorometh- yl)picolinamide C₄₁H₄₃F₃N₈O₇ 64

N-(2-(1-(2-(2-(2- (2-((2-(2,6- dioxopiperidin-3- yl)-1,3-dioxoisoindolin-4- yl)amino)etho- xy)ethoxy)eth- oxy)ethyl)piper-idin-4-yl)-6- methoxy-2H- indazol-5-yl)-6- (trifluorometh-yl)picolinamide C₄₁H₄₅F₃N₈O₉ 65

N-(5-((4-(2-(2-((2- (2,6- dioxopiperidin-3- yl)-1,3- dioxoisoindolin-4-yl)amino)eth- oxy)ethyl)piper- azin-1-yl)methyl)- 1-((1s,4s)-4-(hydroxymeth- yl)cyclohexyl)- 1H- benzo[d]imidazol- 2-yl)-3-(trifluoro-methyl)benzamide C₄₄H₄₉F₃N₈O₇ 66

N-(5-((4-(2-(2- (2-((2-(2,6- dioxopiperidin- 3-yl)-1,3- dioxoisoindolin-4-yl)amino)eth- oxy)ethoxy)eth- yl)piperazin-1- yl)methyl)-1-((1s,4s)-4- (hydroxymeth- yl)cyclohexyl)- 1H- benzo[d]imidazol-2-yl)-3-(trifluoro- methyl)benzamide C₄₆H₅₃F₃N₈O₈ 67

N-(5-((4-((4-((2- (2,6- dioxopiperidin-3- yl)-1,3- dioxoisoindolin-5-yl)oxy)cyclohex- yl)methyl)piper- azin-1-yl)methyl)- 1-((1s,4s)-4-(hydroxymeth- yl)cyclohexyl)- 1H- benzo[d]imidazol- 2-yl)-3-(trifluoro-methyl)benzamide C₄₇H₅₂F₃N₇O₇ 68

N-(1-(3-((2-((2- (2,6- dioxopiperidin-3- yl)-1,3- dioxoisoindolin-5-yl)oxy)eth- yl)(methyl)ami- no)phenyl)-5- (piperidin-1- ylmethyl)-1H-benzo[d]imidazol- 2-yl)-3-(trifluoro- methyl)benzamide C₄₃H₄₀F₃N₇O₆

TABLE 5 Characterization data for exemplary compounds of the presentdisclosure MW; IRAK4 IRAK4 [M + H] + 1 IRAK4 DC50** IC50*** Ex # (2)Dmax (%)* (nM) (nM) Proton NMR data 1 815.851; C C A (400 MHz, DMSO-d6)δ: 12.82 (s, 1H), 11.11 816.64 (s, 1H), 8.50 (d, J = 8.0 Hz, 1H), 8.45(s, 1H), 8.21 (s, 1H), 7.90 (d, J = 8.0 Hz, 1H), 7.82 (d, J = 8.4 Hz,1H), 7.77-7.71 (m, 1H), 7.56- 7.51 (m, 2H), 7.45 (d, J = 2.0 Hz, 1H),7.35 (dd, J = 2.0, 8.4 Hz, 1H), 7.19 (d, J = 8.4 Hz, 1H), 5.11 (dd, J =5.2, 13.2 Hz, 1H), 4.79-4.66 (m, 1H), 4.28 (t, J = 5.6 Hz, 2H), 3.68 (d,J = 7.6 Hz, 2H), 3.52 (s, 1H), 2.93-2.84 (m, 1H), 2.73 (t, J = 5.4 Hz,2H), 2.64-2.56 (m, 2H), 2.55-2.51 (m, 8H), 2.46-2.35 (m, 4H), 2.10- 2.00(m, 1H), 1.98-1.89 (m, 2H), 1.88- 1.80 (m, 1H), 1.74-1.56 (m, 4H) 2860.68 B A A (400 MHz, DMSO-d6) δ: 12.82 (s, 1H), 11.11 (s, 1H),8.55-8.38 (m, 2H), 8.21 (s, 1H), 7.90 (d, J = 8.4 Hz, 1H), 7.82 (d, J =8.4 Hz, 1H), 7.77-7.70 (m, 1H), 7.56-7.49 (m, 2H), 7.45 (d, J = 2.0 Hz,1H), 7.36 (dd, J = 2.4, 8.4 Hz, 1H), 7.18 (d, J = 8.4 Hz, 1H), 5.11 (dd,J = 5.2, 13.0 Hz, 1H), 4.72 (s, 1H), 4.58 (s, 1H), 4.30 (d, J = 4.4 Hz,2H), 3.76 (s, 2H), 3.68 (d, J = 7.2 Hz, 3H), 3.57 (t, J = 6.0 Hz, 3H),3.49 (s, 4H), 2.98-2.79 (m, 2H), 2.63-2.56 (m, 1H), 2.46- 2.38 (m, 6H),2.10-1.99 (m, 2H), 1.94 (d, J = 13.6 Hz, 2H), 1.85 (s, 2H), 1.72-1.56(m, 4H) 3 904.72 A A A (400 MHz, DMSO-d6) δ: 12.83 (s, 1H), 11.12 (s,1H), 8.50 (d, J = 8.0 Hz, 1H), 8.45 (s, 1H), 8.26 (s, 1H), 7.90 (d, J =8.0 Hz, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.77-7.71 (m, 1H), 7.56- 7.49 (m,2H), 7.45 (d, J = 2.0 Hz, 1H), 7.36 (dd, J = 2.0, 8.4 Hz, 1H), 7.17 (d,J = 8.4 Hz, 1H), 5.12 (dd, J = 5.6, 13.2 Hz, 1H), 4.78-4.65 (m, 2H),4.33-4.29 (m, 2H), 3.80-3.76 (m, 2H), 3.68 (br d, J = 7.6 Hz, 3H),3.62-3.55 (m, 4H), 3.54-3.44 (m, 10H), 2.91-2.85 (m, 1H), 2.62-2.58 (m,2H), 2.46-2.34 (m, 6H), 2.09-1.99 (m, 1H), 1.94 (d, J = 12.8 Hz, 2H),1.85 (s, 1H), 1.73-1.57 (m, 4H) 4 948.75 A A A (400 MHz, DMSO-d6) δ:12.83 (s, 1H), 11.12 (s, 1H), 8.49 (d, J = 8.0 Hz, 1H), 8.44 (s, 1H),8.26 (s, 1H), 7.90 (d, J = 7.2 Hz, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.74(t, J = 8.0 Hz, 1H), 7.56- 7.49 (m, 2H), 7.44 (d, J = 2.0 Hz, 1H), 7.35(dd, J = 2.0, 8.4 Hz, 1H), 7.17 (d, J = 8.4 Hz, 1H), 5.12 (dd, J = 5.6,13.2 Hz, 1H), 4.72 (s, 1H), 4.32-4.27 (m, 2H), 3.78-3.75 (m, 2H), 3.68(d, J = 7.6 Hz, 3H), 3.62-3.56 (m, 4H), 3.55-3.51 (m, 4H), 3.51-3.44 (m,10H), 2.92- 2.85 (m, 1H), 2.62-2.57 (m, 2H), 2.47- 2.34 (m, 6H),2.07-1.99 (m, 1H), 1.94 (d, J = 13.2 Hz, 2H), 1.84 (s, 1H), 1.73-1.55(m, 4H) 5 992.79 B B A (400 MHz, DMSO-d6) δ: 12.84 (s, 1H), 11.13 (s,1H), 8.50 (d, J = 8.0 Hz, 1H), 8.45 (s, 1H), 8.25 (s, 1H), 7.90 (d, J =8.0 Hz, 1H), 7.82 (d, J = 8.4 Hz, 1H), 7.74 (t, J = 8.0 Hz, 1H), 7.57-7.50 (m, 2H), 7.45 (d, J = 2.4 Hz, 1H), 7.36 (dd, J = 2.4, 8.4 Hz, 1H),7.19 (d, J = 8.4 Hz, 1H), 5.12 (dd, J = 5.6, 12.8 Hz, 1H), 4.73 (s, 1H),4.33-4.27 (m, 2H), 3.78-3.75 (m, 2H), 3.69 (d, J = 7.6 Hz, 3H),3.62-3.56 (m, 4H), 3.55-3.44 (m, 18H), 2.93-2.85 (m, 1H), 2.63- 2.57 (m,2H), 2.47-2.38 (m, 6H), 2.09- 2.01 (m, 1H), 1.94 (d, J = 12.8 Hz, 2H),1.85 (s, 1H), 1.71-1.59 (m, 4H) 6 846.5 N.D. E A (400 MHz, CD3OD) δ:8.59-8.49 (m, 3H), 7.83 (br d, J = 7.6 Hz, 1H), 7.76-7.66 (m, 2H), 7.56(br d, J = 8.4 Hz, 1H), 7.50 (s, 1H), 7.30 (br d, J = 7.6 Hz, 1H), 7.16(s, 1H), 7.10 (br d, J = 8.6 Hz, 1H), 5.17 (br dd, J = 5.2, 13.2 Hz,1H), 4.54-4.38 (m, 2H), 4.27 (br s, 2H), 3.94- 3.84 (m, 4H), 3.78 (br t,J = 4.8 Hz, 2H), 3.73- 3.63 (m, 2H), 2.99-2.45 (m, 15H), 2.23- 1.96 (m,5H), 1.89-1.71 (m, 4H). 7 422.83 C E C 8 422.83 N.D. N.D. N.D. 9 869.65A A A (400 MHz, DMSO-d6) δ: 12.21-13.74 (m, 1H), 11.07 (s, 1H), 8.50 (d,J = 7.6 Hz, 1H), 8.45 (s, 1 H), 7.91 (d, J = 8.0 Hz, 1H), 7.75 (t, J =7.6 Hz, 1H), 7.58-7.68 (m, 3 H), 7.33 (s, 2 H), 7.25 (d, J = 8.4 Hz,1H), 5.06 (dd, J = 5.2, 12.8 Hz, 1H), 4.68-4.80 (m, 1H), 4.06 (d, J =12.4 Hz, 4H), 3.69 (d, J = 7.2 Hz, 3H), 2.81- 3.02 (m, 8H), 2.58-2.69(m, 2H), 2.33 (br s, 1H), 1.91-2.08 (m, 5H), 1.75-1.90 (m, 4H),1.58-1.74 (m, 5 H), 1.14-1.28 (m, 3H), 1.05 (t, J = 7.2 Hz, 2H). 10913.7 A B A (400 MHz, DMSO-d6) δ: 13.30-12.54 (m, 1H), 11.39-11.03 (m,1H), 10.27-9.80 (m, 1H), 8.69-8.30 (m, 2H), 7.99-7.85 (m, 2H), 7.76 (t,J = 8.0 Hz, 1H), 7.72-7.59 (m, 2H), 7.54 (d, J = 2.0 Hz, 1H), 7.45-7.28(m, 2H), 5.14 (dd, J = 5.2, 12.8, Hz, 1H), 4.81-4.69 (m, 1H), 4.57 (s,2H), 4.29-4.08 (m, 3H), 3.70- 3.56 (m, 10H), 3.09-2.81 (m, 7H),2.65-2.54 (m, 6H), 2.10-2.03 (m, 1H), 2.00-1.82 (m, 6H), 1.73-1.60 (m,4H), 1.41 (d, J = 11.6 Hz, 2H). 11 1030.84 A E D (400 MHz, DMSO-d6) δ:12.94 (s, 1H), 8.96- 9.00 (m, 1H), 8.60 (t, J = 6.0 Hz, 1H), 8.50 (d, J= 8.0 Hz, 1H), 8.45 (s, 1H), 7.92 (d, J = 7.6 Hz, 1H), 7.85 (br d, J =10.0 Hz, 1H), 7.76 (t, J = 7.6 Hz, 1H), 7.65 (d, J = 8.4 Hz, 1H), 7.60(s, 1H), 7.35-7.46 (m, 5H), 7.31 (br d, J = 8.8 Hz, 1H), 4.72 (br d, J =10.4 Hz, 2H), 4.58 (d, J = 9.6 Hz, 1H), 4.33-4.47 (m, 4H), 4.19-4.31 (m,2H), 3.96-4.15 (m, 7H), 3.71-3.79 (m, 7H), 2.96- 3.38 (m, 2H), 2.43 (s,4H), 2.02-2.12 (m, 1H), 1.81-2.01 (m, 5H), 1.55-1.80 (m, 5H), 0.87-1.01(m, 11H). 12 1074.88 N.D. E B (400 MHz, DMSO-d6) δ: 8.96 (s, 1H), 8.59(t, J = 6.0 Hz, 1H), 8.49 (d, J = 7.6 Hz, 1H), 8.44 (s, 1H), 8.21-8.16(m, 1H), 7.89 (d, J = 8.0 Hz, 1H), 7.74 (t, J = 7.6 Hz, 1H), 7.55-7.49(m, 2H), 7.38 (s, 4H), 7.17 (d, J = 8.4 Hz, 1H), 4.72 (s, 1H), 4.56 (d,J = 9.6 Hz, 1H), 4.43 (t, J = 8.0 Hz, 1H), 4.40-4.32 (m, 2H), 4.28-4.18(m, 1H), 3.96 (s, 2H), 3.72-3.62 (m, 4H), 3.62- 3.57 (m, 4H), 3.56-3.51(m, 5H), 3.48 (s, 3H), 2.52 (d, J = 1.6 Hz, 8H), 2.43 (s, 3H), 2.40-2.35 (m, 2H), 2.11-2.00 (m, 1H), 1.98- 1.79 (m, 4H), 1.74-1.54 (m, 4H),0.98-0.86 (m, 9H) 13 1118.92 N.D. E D (400 MHz, DMSO-d6) δ: 8.97 (s,1H), 8.60 (t, J = 6.0 Hz, 1H), 8.50 (d, J = 7.6 Hz, 1H), 8.45 (s, 1H),8.21-8.12 (m, 1H), 7.89 (d, J = 7.6 Hz, 1H), 7.74 (t, J = 7.6 Hz, 1H),7.57-7.47 (m, 2H), 7.41 (d, J = 9.2 Hz, 1H), 7.39 (s, 3H), 7.18 (d, J =9.2 Hz, 1H), 4.78-4.67 (m, 1H), 4.56 (d, J = 9.6 Hz, 1H), 4.47-4.40 (m,2H), 4.39- 4.30 (m, 2H), 4.29-4.15 (m, 2H), 3.96 (s, 2H), 3.70-3.64 (m,4H), 3.61-3.53 (m, 8H), 3.50-3.44 (m, 7H), 2.52 (d, J = 2.0 Hz, 8H),2.43 (s, 3H), 2.37 (s, 2H), 2.08-2.02 (m, 1H), 1.96-1.83 (m, 4H),1.70-1.58 (m, 4H), 0.96- 0.91 (m, 9H) 14 1162.95 N.D. E A (400 MHz,DMSO-d6) δ: 8.99 (s, 1H), 8.60 (t, J = 6.0 Hz, 1H), 8.50 (d, J = 7.6 Hz,1H), 8.45 (s, 1H), 7.92 (br d, J = 8.0 Hz, 1H), 7.76 (t, J = 7.6 Hz,1H), 7.65 (d, J = 8.4 Hz, 1H), 7.59 (s, 1H), 7.35-7.50 (m, 6H), 7.31 (brd, J = 8.0 Hz, 1H), 4.73 (br d, J = 10.6 Hz, 2H), 4.56 (d, J = 9.4 Hz,1H), 4.33-4.46 (m, 4H), 4.20-4.31 (m, 2H), 3.90-4.12 (m, 7H), 3.59-3.73(m, 19H), 2.98- 3.35 (m, 2H), 2.44 (s, 4H), 2.02-2.12 (m, 1H), 1.81-2.01(m, 5H), 1.57-1.77 (m, 5H), 0.85-1.00 (m, 11H). 25 792.62 N.D. E B (400MHz, DMSO-d6) δ: 13.27 (s, 1H), 11.11 (s, 1H), 9.38 (dd, J = 1.6, 7.2Hz, 1H), 9.14 (dd, J = 1.6, 4.4 Hz, 1H), 8.73 (s, 1H), 8.44 (s, 1H),8.23 (s, 1H), 7.83 (d, J = 8.4 Hz, 1H), 7.79 (dd, J = 2.4, 8.8 Hz, 1H),7.67 (d, J = 8.4 Hz, 1H), 7.46 (d, J = 2.4 Hz, 1H), 7.40-7.35 (m, 2H),6.62 (s, 1H), 5.11 (dd, J = 5.2, 12.8 Hz, 1H), 4.41-4.27 (m, 2H),3.83-3.78 (m, 2H), 3.63- 3.59 (m, 3H), 3.58-3.53 (m, 6H), 3.24- 3.19 (m,3H), 2.93-2.80 (m, 2H), 2.62-2.56 (m, 2H), 2.55-2.53 (m, 3H), 2.37 (s,3H), 2.07-2.00 (m, 1H) 26 836.66 N.D. E D (400 MHz, DMSO-d6) δ: 13.25(s, 1H), 11.11 (s, 1H), 9.38 (dd, J = 1.6, 7.2 Hz, 1H), 9.14 (dd, J =1.6, 4.2 Hz, 1H), 8.72 (s, 1H), 8.43 (s, 1H), 8.22 (s, 1H), 7.81-7.75(m, 2H), 7.67 (d, J = 8.8 Hz, 1H), 7.43 (d, J = 2.0 Hz, 1H), 7.39- 7.32(m, 2H), 6.62 (s, 1H), 5.10 (dd, J = 5.6, 13.2 Hz, 1H), 4.35-4.25 (m,2H), 3.82-3.78 (m, 2H), 3.62-3.59 (m, 3H), 3.56-3.51 (m, 10H), 3.30-3.16(m, 3H), 2.85 (d, J = 11.6 Hz, 2H), 2.63-2.57 (m, 2H), 2.55-2.54 (m,3H), 2.37 (s, 3H), 2.07-1.99 (m, 1H) 27 1006.83 N.D. E D (400 MHz,DMSO-d6) δ: 13.26 (s, 1H), 9.43- 9.33 (m, 1H), 9.16-9.09 (m, 1H), 8.98(s, 1H), 8.75-8.68 (m, 1H), 8.62 (t, J = 6.1 Hz, 1H), 8.43 (s, 1H), 8.19(s, 1H), 7.81-7.74 (m, 1H), 7.67 (d, J = 8.4 Hz, 1H), 7.48-7.33 (m, 6H),6.63 (s, 1H), 4.58 (d, J = 9.5 Hz, 1H), 4.50-4.34 (m, 3H), 4.29-4.21 (m,1H), 3.99 (s, 2H), 3.69-3.55 (m, 21H), 2.44 (s, 3H), 2.36 (s, 3H),2.11-2.02 (m, 1H), 1.95-1.86 (m, 1H), 1.04-0.90 (m, 9H) 28 1050.86 N.D.E D (400 MHz, DMSO-d6) δ: 13.25 (s, 1H), 9.43- 9.32 (m, 1H), 9.16-9.08(m, 1H), 8.97 (s, 1H), 8.74-8.67 (m, 1H), 8.59 (t, J = 5.9 Hz, 1H), 8.43(s, 1H), 8.18 (s, 1H), 7.80-7.74 (m, 1H), 7.67 (d, J = 8.6 Hz, 1H),7.47-7.32 (m, 6H), 6.63 (s, 1H), 4.60-4.53 (m, 1H), 4.48- 4.37 (m, 2H),4.26-4.20 (m, 1H), 4.01-3.93 (m, 2H), 3.77-3.47 (m, 24H), 2.54 (br d, J= 5.3 Hz, 4H), 2.43 (s, 3H), 2.36 (s, 3H), 2.10- 2.03 (m, 1H), 1.95-1.87(m, 1H), 0.97-0.91 (m, 9H) 29 637.55 N.D. E D (400 MHz, DMSO-d6) δ:11.10 (s, 1H), 8.94 (d, J = 1.6 Hz, 1H), 8.55 (s, 1H), 8.27 (d, J = 7.2Hz, 1H), 8.21 (s, 1H), 8.05 (dd, J = 2.0, 8.4 Hz, 1H), 7.83 (d, J = 8.4Hz, 1H), 7.76 (d, J = 8.4 Hz, 1H), 7.46 (d, J = 2.0 Hz, 1H), 7.37 (dd, J= 2.4, 8.4 Hz, 1H), 5.12 (dd, J = 5.2, 12.8 Hz, 1H), 4.29 (t, 7 = 5.6Hz, 2H), 4.12 (d, J = 7.2 Hz, 1H), 2.93-2.84 (m, 1H), 2.72 (t, J = 5.6Hz, 2H), 2.61 (d, J = 2.8 Hz, 2H), 2.55-2.52 (m, 8H), 2.31-2.25 (m, 1H),2.09-2.00 (m, 3H), 1.92-1.83 (m, 2H), 1.49-1.32 (m, 4H) 30 681.59 N.D. ED (400 MHz, DMSO-d6) δ: 11.19-11.01 (m, 1H), 8.94 (d, J = 1.6 Hz, 1H),8.55 (s, 1H), 8.27 (d, J = 7.6 Hz, 1H), 8.19 (s, 1H), 8.05 (dd, J = 1.6,8.8 Hz, 1H), 7.84 (d, J = 8.4 Hz, 1H), 7.76 (d, J = 8.8 Hz, 1H), 7.45(d, J = 2.4 Hz, 1H), 7.37 (dd, J = 2.4, 8.4 Hz, 1H), 5.11 (dd, J = 5.6,12.8 Hz, 1H), 4.38-4.26 (m, 2H), 4.18-4.05 (m, 1H), 3.79-3.75 (m, 2H),3.60-3.56 (m, 6H), 2.95-2.85 (m, 1H), 2.63- 2.55 (m, 2H), 2.47-2.36 (m,6H), 2.31- 2.25 (m, 1H), 2.10-1.98 (m, 3H), 1.87 (d, J = 11.6 Hz, 2H),1.48-1.29 (m, 4H) 31 725.63 N.D. E E (400 MHz, DMSO-d6) δ: 11.15-11.05(m, 1H), 8.94 (d, J = 1.6 Hz, 1H), 8.55 (s, 1H), 8.26 (d, J = 7.6 Hz,1H), 8.19 (s, 1H), 8.05 (dd, J = 1.6, 8.8 Hz, 1H), 7.84 (d, J = 8.4 Hz,1H), 7.76 (d, J = 8.8 Hz, 1H), 7.46 (d, J = 2.4 Hz, 1H), 7.38 (dd, J =2.4, 8.4 Hz, 1H), 5.11 (dd, J = 5.6, 12.8 Hz, 1H), 4.36-4.25 (m, 2H),4.18-4.03 (m, 1H), 3.82-3.78 (m, 2H), 3.63-3.56 (m, 6H), 3.54-3.52 (m,4H), 2.94- 2.85 (m, 1H), 2.60-2.54 (m, 2H), 2.46- 2.41 (m, 6H),2.30-2.23 (m, 1H), 2.07-1.98 (m, 3H), 1.90-1.80 (m, 2H), 1.48-1.26 (m,4H) 32 769.67 N.D. E E (400 MHz, DMSO-d6) δ: 11.11 (s, 1H), 8.93 (d, J =1.6 Hz, 1H), 8.54 (s, 1H), 8.27 (d, J = 7.6 Hz, 1H), 8.20 (s, 1H), 8.05(dd, J = 1.6, 8.8 Hz, 1H), 7.84 (d, J = 8.4 Hz, 1H), 7.76 (d, J = 8.8Hz, 1H), 7.46 (d, J = 2.0 Hz, 1H), 7.38 (dd, J = 2.0, 8.4 Hz, 1H), 5.11(dd, J = 5.6, 13.2 Hz, 1H), 4.36-4.28 (m, 2H), 4.16-4.06 (m, 1H),3.82-3.78 (m, 2H), 3.62-3.59 (m, 6H), 3.55 (d, J = 2.8 Hz, 4H),3.49-3.48 (m, 4H), 2.94-2.86 (m, 1H), 2.62-2.55 (m, 2H), 2.47-2.37 (m,6H), 2.31-2.25 (m, 1H), 2.08- 1.98 (m, 3H), 1.86 (d, J = 11.2 Hz, 2H),1.49- 1.27 (m, 4H) 33 813.7 N.D. E E (400 MHz, DMSO-d6) δ: 11.11 (s,1H), 8.93 (d, J = 1.2 Hz, 1H), 8.54 (s, 1H), 8.27 (d, J = 7.2 Hz, 1H),8.19 (s, 1H), 8.05 (dd, J = 1.6, 8.8 Hz, 1H), 7.83 (d, J = 8.4 Hz, 1H),7.76 (d, J = 8.8 Hz, 1H), 7.45 (d, J = 2.2 Hz, 1H), 7.37 (dd, J = 2.4,8.4 Hz, 1H), 5.11 (dd, J = 5.6, 12.8 Hz, 1H), 4.35-4.29 (m, 2H),4.16-4.07 (m, 1H), 3.81-3.78 (m, 2H), 3.62-3.59 (m, 4H), 3.57-3.54 (m,6H), 3.52-3.51 (m, 4H), 3.48-3.47 (m, 4H), 2.91-2.82 (m, 1H), 2.63- 2.55(m, 2H), 2.44 (t, J = 6.0 Hz, 6H), 2.31- 2.27 (m, 1H), 2.08-1.98 (m,3H), 1.87 (d, J = 11.2 Hz, 2H), 1.48-1.28 (m, 4H) 34 745.38 N.D. E E(400 MHz, DMSO-d6) δ: 11.09 (s, 1H), 8.93 (d, J = 1.6 Hz, 1H), 9.02-8.86(m, 1H), 8.55 (s, 1H), 8.26 (d, J = 7.6 Hz, 1H), 8.05 (dd, J = 1.6, 8.8Hz, 1H), 7.84 (d, J = 8.4 Hz, 1H), 7.76 (d, J = 8.8 Hz, 1H), 7.47 (d, J= 2.0 Hz, 1H), 7.39 (dd, J = 2.0, 8.4 Hz, 1H), 5.10 (dd, J = 5.6, 12.8Hz, 1H), 4.33 (dd, J = 3.2, 5.2 Hz, 2H), 4.19-4.02 (m, 1H), 3.89-3.72(m, 4H), 3.33 (s, 2H), 3.15 (d, J = 4.8 Hz, 4H), 2.91- 2.79 (m, 1H),2.53 (d, J = 6.4 Hz, 4H), 2.52 (s, 2H), 2.40-2.28 (m, 1H), 2.05-1.93 (m,3H), 1.77 (d, J = 10.0 Hz, 2H), 1.46-1.28 (m, 4H) 35 745.56 N.D. E E(400 MHz, DMSO-d6) δ: 11.13-11.07 (m, 1H), 9.05 (s, 1H), 8.55 (s, 1H),8.09 (d, J = 7.2 Hz, 1H), 8.04 (dd, J = 1.6, 8.8 Hz, 1H), 7.85- 7.72 (m,2H), 7.42 (s, 1H), 7.40-7.33 (m, 1H), 5.11-5.05 (m, 1H), 4.36-4.32 (m,2H), 4.31-4.22 (m, 2H), 3.87-3.79 (m, 6H), 3.52- 3.50 (m, 2H), 3.17 (s,3H), 2.61-2.56 (m, 2H), 2.54-2.53 (m, 3H), 2.24-2.16 (m, 1H), 2.04-1.94(m, 1H), 1.90-1.77 (m, 4H), 1.67- 1.56 (m, 2H), 1.53-1.44 (m, 2H) 36789.43 N.D. E E (400 MHz, DMSO-d6) δ: 11.10 (s, 1H), 8.93 (d, J = 1.2Hz, 1H), 8.58-8.52 (m, 1H), 8.26 (d, J = 7.6 Hz, 1H), 8.05 (dd, J = 1.6,8.8 Hz, 1H), 7.84 (d, J = 8.4 Hz, 1H), 7.76 (d, J = 8.8 Hz, 1H), 7.46(d, J = 2.4 Hz, 1H), 7.38 (dd, J = 2.4, 8.4 Hz, 1H), 5.11 (dd, J = 5.2,12.8 Hz, 1H), 4.39-4.26 (m, 2H), 4.19-4.03 (m, 1H), 3.84-3.78 (m, 2H),3.74 (t, J = 6.0 Hz, 2H), 3.66-3.61 (m, 2H), 3.60-3.55 (m, 2H), 3.30-3.28 (m, 2H), 3.15 (s, 4H), 2.94-2.81 (m, 1H), 2.61-2.53 (m, 6H),2.42-2.35 (m, 1H), 2.09-1.96 (m, 3H), 1.83 (d, J = 10.0 Hz, 2H),1.51-1.25 (m, 4H) 37 789.43 E (400 MHz, DMSO-d6) δ: 11.10 (s, 1H), 9.06(d, J = 1.6 Hz, 1H), 8.55 (s, 1H), 8.09 (d, J = 6.8 Hz, 1H), 8.03 (dd, J= 1.6, 8.8 Hz, 1H), 7.77 (dd, J = 8.4, 18.0 Hz, 2H), 7.41 (d, J = 2.0Hz, 1H), 7.36-7.28 (m, 1H), 5.11 (dd, J = 5.2, 12.8 Hz, 1H), 4.36-4.21(m, 3H), 3.83- 3.78 (m, 2H), 3.76 (t, J = 6.0 Hz, 2H), 3.65- 3.61 (m,2H), 3.61-3.57 (m, 2H), 3.34 (s, 2H), 3.18 (s, 4H), 2.96-2.82 (m, 1H),2.64- 2.55 (m, 2H), 2.55-2.52 (m, 4H), 2.29-2.19 (m, 1H), 2.07-2.00 (m,1H), 1.95-1.80 (m, 4H), 1.65 (dd, J = 3.6, 8.0 Hz, 2H), 1.58-1.47 (m,2H) 38 833.45 E (400 MHz, DMSO-d6) δ: 1.31-1.46 (m, 4 H), 1.85 (d, J =10.4 Hz, 2 H), 1.99-2.08 (m, 3 H), 2.57 (s, 3 H), 2.83-2.95 (m, 1 H),3.14 (d, J = 4.8 Hz, 4 H), 3.30 (s, 3 H), 3.52-3.58 (m, 8 H), 3.59-3.64(m, 3 H), 3.72-3.83 (m, 4 H), 4.12 (d, J = 7.6 Hz, 1 H), 4.30-4.34 (m, 2H), 5.11 (m, 1 H), 7.38 (m, 1 H), 7.46 (d, J = 2.4 Hz, 1 H), 7.76 (d, J= 8.8 Hz, 1 H), 7.83 (d, J = 8.4 Hz, 1 H), 8.06 (m, 1 H), 8.28 (d, J =7.6 Hz, 1 H), 8.34 (s, 1 H), 8.55 (s, 1 H), 8.94 (s, 1 H), 11.11 (s, 1H) 39 833.45 E (400 MHz, DMSO-d6) δ: 1.50-1.69 (m, 5 H), 1.88 (d, J =8.8 Hz, 5 H), 2.00-2.11 (m, 2 H), 2.25 (s, 2 H), 2.31-2.36 (m, 3 H),2.66-2.69 (m, 2 H), 2.88 (d, J = 12.0 Hz, 1 H), 3.19 (s, 5 H), 3.55 (s,6 H), 3.58-3.61 (m, 2 H), 3.73- 3.79 (m, 4 H), 4.30 (d, J = 3.6 Hz, 3H), 5.12 (m, 1 H), 7.34 (m, 1 H), 7.43 (d, J = 2.0 Hz, 1 H), 7.76 (d, J= 8.8 Hz, 1 H), 7.81 (d, J = 8.4 Hz, 1 H), 8.05 (m, 1 H), 8.12 (d, J =6.8 Hz, 1 H), 8.56 (s, 1 H), 9.08 (s, 1 H), 11.11 (s, 1 H) 40 877.49N.D. E E (400 MHz, DMSO-d6) δ: 11.11 (s, 1H), 9.08 (s, 1H), 8.56 (s,1H), 8.28 (s, 1H), 8.12 (d, J = 6.8 Hz, 1H), 8.05 (m, 1H), 7.86-7.72 (m,2H), 7.44 (d, J = 2.0 Hz, 1H), 7.35 (m, 1H), 5.12 (m, 1H), 4.33-4.27 (m,3H), 3.79-3.72 (m, 4H), 3.58-3.51 (m, 14H), 3.19 (s, 4H), 2.93-2.85 (m,1H), 2.64-2.57 (m, 4H), 2.25 (s, 1H), 2.08-1.82 (m, 6H), 1.70-1.46 (m,5H) 41 877.48 N.D. E E (400 MHz, DMSO-d6) δ: 8.63 (s, 1H), 8.04 (s, 1H),7.84-7.77 (m, 2H), 7.73-7.67 (m, 1H), 7.30 (d, J = 2.4 Hz, 1H),7.19-7.15 (m, 2H), 5.73-5.61 (m, 1H), 4.89 (m, 1H), 4.25-4.09 (m, 3H),3.89-3.77 (m, 4H), 3.68-3.51 (m, 13H), 3.16 (t, J = 6.4 Hz, 6H),2.88-2.56 (m, 8H), 2.38 (s, 1H), 2.24-2.17 (m, 2H), 2.13- 2.07 (m, 1H),1.93-1.85 (m, 2H), 1.26-1.17 (m, 2H) 42 947.69 N.D. E D (400 MHz,DMSO-d6) δ: ppm 12.83 (br s, 1 H) 11.12 (s, 1 H) 8.50 (d, J = 7.88 Hz, 1H) 8.43 (s, 1 H) 8.30 (s, 1 H) 7.90 (br d, J = 7.64 Hz, 1 H) 7.81 (d, J= 8.26 Hz, 1 H) 7.74 (t, J = 7.68 Hz, 1 H) 7.56 (d, J = 8.38 Hz, 1 H)7.51 (s, 1 H) 7.43 (d, J = 2.14 Hz, 1 H) 7.34 (dd, J = 8.32, 2.31 Hz, 1H) 7.15-7.24 (m, 1 H) 5.12 (dd, J = 12.88, 5.38 Hz, 1 H) 4.72 (br s, 1H) 4.24-4.32 (m, 2 H) 3.72-3.79 (m, 2 H) 3.68 (br d, J = 7.50 Hz, 2 H)3.45-3.59 (m, 18 H)1.40 (br s, 2 H) 2.89 (ddd, J = 17.40, 14.13, 5.50Hz, 1 H) 2.52-2.63 (m, 3 H) 2.30-2.35 (m, 4 H) 2.00-2.09 (m, 2 H)1.86-1.96 (m, 2 H) 1.60-1.77 (m, 4 H) 1.49 (br d, J = 5.00 Hz, 4H) 43903.66 N.D. E N.D. (400 MHz, DMSO-d6) δ: δ ppm 12.83 (br s, 1 H) 11.12(s, 1 H) 8.50 (d, J = 7.88 Hz, 1 H) 8.43 (s, 1 H) 8.30 (s, 1 H) 7.90 (brd, J = 7.64 Hz, 1 H) 7.81 (d, J = 8.26 Hz, 1 H) 7.74 (t, J = 7.68 Hz, 1H) 7.56 (d, J = 8.38 Hz, 1 H) 7.51 (s, 1 H) 7.43 (d, J = 2.14 Hz, 1 H)7.34 (dd, J = 8.32, 2.31 Hz, 1 H) 7.15-7.24 (m, 1 H) 5.12 (dd, J =12.88, 5.38 Hz, 1 H) 4.72 (br s, 1 H) 4.24-4.32 (m, 2 H) 3.72-3.79 (m, 2H) 3.68 (br d, J = 7.50 Hz, 2 H) 3.45-3.59 (m, 18 H) 2.89 (ddd, J =17.40, 14.13, 5.50 Hz, 1 H)1.37 (br s, 1 H) 2.52-2.63 (m, 3 H) 2.67-2.67 (m, 3 H) 2.56-2.67 (m, 2 H) 2.33-2.35 (m, 2H) 1.64-2.01 (m, 12 H)44 859.62 N.D. E E (400 MHz, DMSO-d6) δ ppm 12.83 (br s, 1 H) 11.12 (s,1 H) 8.50 (d, J = 7.88 Hz, 1 H) 8.43 (s, 1 H) 8.30 (s, 1 H) 7.90 (br d,J = 7.64 Hz, 1 H) 7.81 (d, J = 8.26 Hz, 1 H) 7.74 (t, J = 7.68 Hz, 1 H)7.56 (d, J = 8.38 Hz, 1 H) 7.51 (s, 1 H) 7.43 (d, J = 2.14 Hz, 1 H) 7.34(dd, J = 8.32, 2.31 Hz, 1 H) 7.15-7.24 (m, 1 H) 5.12 (dd, J = 12.88,5.38 Hz, 1 H) 4.72 (br s, 1 H) 4.24- 4.32 (m, 2 H)1.39-1.49 (br d, J =5.00 Hz, 6 H) 3.72-3.79 (m, 2 H) 3.68 (br d, J = 7.50 Hz, 2 H) 3.45-3.59(m, 10 H) 2.89 (ddd, J = 17.40, 14.13, 5.50 Hz, 1 H) 2.52-2.63 (m, 3 H)2.30- 2.35 (m, 4 H) 2.00-2.09 (m, 2 H) 1.86- 1.96 (m, 2 H) 1.66-1.77 (m,4 H) 45 736.35 N.D. N.D. E (400 MHz, DMSO-d6) δ = 1.72-1.84 (m, 4 H),2.00-2.11 (m, 2 H), 2.12-2.29 (m, 2 H), 2.48- 2.66 (m, 2 H), 2.67-2.98(m, 3 H), 3.83 (d, J = 7.2 Hz, 2 H), 3.89-3.99 (m, 2 H), 4.25- 4.36 (m,2 H), 4.57-4.74 (m, 1 H), 4.96 (dd, J = 12.4, 5.2 Hz, 1 H), 6.93-7.02(m, 1 H), 7.09 (dd, J = 8.0, 2.4 Hz, 1 H), 7.22 (dd, J = 8.4, 2.4 Hz, 1H), 7.28-7.33 (m, 1 H), 7.38 (d, J = 2.4 Hz, 1 H), 7.54-7.65 (m, 1 H),7.71- 7.80 (m, 2 H), 8.04 (s, 1 H), 8.48 (d, J = 7.6 Hz, 1 H), 8.57 (s,1 H), 12.55-12.94 (m, 1 H). 46 780.56 N.D. E E (400 MHz, DMSO-d6) δ =1.71-1.84 (m, 4 H), 2.02-2.09 (m, 2 H), 2.11-2.24 (m, 2 H), 2.47- 2.64(m, 2 H), 2.68-2.96 (m, 3 H), 3.71- 3.82 (m, 6 H), 3.87-3.95 (m, 2 H),4.18-4.26 (m, 2 H), 4.62-4.80 (m, 1 H), 4.97 (dd, J = 12.23, 5.2 Hz, 1H), 6.95 (td, J = 8.8, 2.4 Hz, 1 H), 7.03-7.09 (m, 1 H), 7.14 (dd, J =8.4, 2.0 Hz, 1 H), 7.23 (d, J = 2.0 Hz, 1 H), 7.32 (dd, J = 8.8, 4.2 Hz,1 H), 7.55-7.62 (m, 1 H), 7.68- 7.79 (m, 2 H), 8.11-8.19 (m, 1 H), 8.48(d, J = 8.0 Hz, 1 H), 8.56 (s, 1 H), 12.43-12.98 (m, 1 H). 47 824.6 N.D.E E (400 MHz, DMSO-d6) δ = 1.69-1.85 (m, 4 H), 1.97-2.09 (m, 2 H),2.11-2.23 (m, 2 H), 2.45- 2.63 (m, 2 H), 2.66-2.98 (m, 3 H), 3.67- 3.79(m, 10 H), 3.85-3.93 (m, 2 H), 4.16- 4.25 (m, 2 H), 4.64-4.81 (m, 1 H),4.92-5.01 (m, 1 H), 6.95-7.03 (m, 1 H), 7.04-7.12 (m, 1 H), 7.14-7.21(m, 1 H), 7.31-7.37 (m, 1 H), 7.55-7.62 (m, 1 H), 7.75 (d, J = 8.4 Hz, 2H), 8.08-8.15 (m, 1 H), 8.45-8.51 (m, 1 H), 8.56 (s, 1 H), 12.35-12.98(m, 1 H) 48 868.64 N.D. E E (400 MHz, DMSO-d6) δ = 1.71-1.87 (m, 4 H),1.99-2.10 (m, 2 H), 2.12-2.22 (m, 2 H), 2.43- 2.60 (m, 2 H), 2.69-3.01(m, 3 H), 3.58- 3.76 (m, 14 H), 3.84-3.93 (m, 2 H), 4.18- 4.28 (m, 2 H),4.64-4.79 (m, 1 H), 4.87-5.02 (m, 1 H), 6.94-7.14 (m, 2 H), 7.18-7.26(m, 1 H), 7.32-7.39 (m, 2 H), 7.55-7.62 (m, 1 H), 7.73-7.80 (m, 2 H),8.24-8.35 (m, 1 H), 8.45-8.51 (m, 1 H), 8.54-8.59 (m, 1 H), 12.29-12.92(m, 1 H). 49 817.58 N.D. E E (400 MHz, DMSO-d6) δ: 11.10 (s, 1H), 8.35-8.25 (m, 2H), 7.83 (br d, J = 7.2 Hz, 1H), 7.76 (d, J = 8.3 Hz, 1H),7.69-7.62 (m, 1H), 7.44- 7.34 (m, 3H), 7.29-7.18 (m, 2H), 7.13-7.02 (m,1H), 6.96 (br d, J = 1.1 Hz, 1H), 6.90- 6.80 (m, 2H), 5.10 (dd, J = 5.4,12.8 Hz, 1H), 4.25-4.12 (m, 2H), 3.71-3.65 (m, 2H), 3.62- 3.45 (m, 10H),2.96 (s, 3H), 2.91-2.82 (m, 1H), 2.63-2.54 (m, 1H), 2.09-1.96 (m, 1H) 50729.49 N.D. E E (300 MHz, DMSO-d6) δ ppm 11.11 (br s, 1 H) 8.24-8.37 (m,2 H) 7.81 (br d, J = 7.96 Hz, 1 H) 7.73 (d, J = 8.24 Hz, 1 H) 7.62 (t, J= 7.82 Hz, 1 H) 7.40-7.48 (m, 2 H) 7.37 (d, J = 2.28 Hz, 1 H) 7.19-7.30(m, 2 H) 7.02-7.15 (m, 2 H) 6.85-7.00 (m, 2 H) 5.11 (dd, J = 12.94, 5.26Hz, 1 H) 4.38 (br s, 2 H) 3.05 (s, 3 H) 3.83 (br s, 2 H) 2.80-2.98 (m, 2H) 2.73 (s, 1 H) 2.24-2.32 (m, 1 H) 2.06 (br d, J = 11.62 Hz, 1 H) 51773.53 N.D. E E (400 MHz, DMSO-d6) δ ppm 11.11 (br s, 1 H) 8.28-8.35 (m,2 H) 7.84 (br d, J = 7.58 Hz, 1 H) 7.76 (d, J = 8.30 Hz, 1 H) 7.66 (t, J= 7.76 Hz, 1 H) 7.36-7.44 (m, 3 H) 7.19-7.28 (m, 2 H) 7.05-7.14 (m, 2 H)6.99 (br s, 1 H) 6.83- 6.91 (m, 2 H) 5.11 (dd, J = 12.84, 5.50 Hz, 1 H)4.24 (br s, 2 H) 3.74 (br s, 2 H) 3.65-3.69 (m, 2 H) 3.58 (br d, J =5.14 Hz, 2 H) 2.98 (s, 4 H) 2.88 (br d, J = 13.94 Hz, 1 H) 2.68 (s, 2 H)2.33 (s, 2 H) 2.00-2.07 (m, 1 H). 52 861.62 N.D. E E (400 MHz, DMSO-d6)δ: 11.10 (br s, 1H), 8.34-8.24 (m, 2H), 7.87-7.80 (m, 1H), 7.80- 7.75(m, 1H), 7.72-7.62 (m, 1H), 7.46- 7.34 (m, 3H), 7.32-7.26 (m, 1H),7.25-7.16 (m, 1H), 7.15-7.04 (m, 1H), 6.95 (br s, 1H), 6.89-6.79 (m,2H), 5.16-5.03 (m, 1H), 4.31- 4.16 (m, 1H), 3.73-3.68 (m, 2H), 3.44 (s,16H), 3.00-2.92 (m, 3H), 2.08-1.97 (m, 1H) 53 868.59 N.D. E E (400 MHz,CDCl3) δ 12.56-12.88 (m, 1 H), 9.63-9.98 (m, 1 H), 8.51 (s, 1 H), 8.39(d, J = 8.0 Hz, 1 H), 7.84 (d, J = 8.4 Hz, 1 H), 7.69 (d, J = 7.6 Hz, 1H), 7.60-7.66 (m, 4 H), 7.48- 7.56 (m, 2 H), 7.44 (d, J = 2.4 Hz, 1 H),7.28- 7.32 (m, 2 H), 7.19 (s, 2 H), 5.05 (dd, J = 12.4, 5.2 Hz, 1 H),4.29 (t, J = 4.46 Hz, 2 H), 3.94 (t, J = 4.8 Hz, 2 H), 3.65-3.75 (m, 6H), 3.32- 3.51 (m, 2 H), 2.73-2.99 (m, 4 H), 2.67 (s, 4 H), 2.46 (s, 4H), 2.00-2.35 (m, 2 H). 54 898.6 N.D. E E (400 MHz, CDCl3)δ 12.42-12.92(m, 1 H), 9.90 (s, 1 H), 8.54 (s, 1 H), 8.42 (d, J = 8.0 Hz, 1 H), 7.84(d, J = 8.4 Hz, 1 H), 7.70 (d, J = 7.2 Hz, 1 H), 7.52 (t, J = 8.4 Hz, 2H), 7.45 (d, J = 2.0 Hz, 1 H), 7.28-7.32 (m, 2 H), 7.16- 7.24 (m, 4 H),7.05-7.10 (m, 1 H), 5.05 (dd, J = 12.4, 5.2 Hz, 1 H). 4.29 (s, 2 H),3.93 (t, J = 4.4 Hz, 2 H), 3.89 (s, 3 H), 3.72 (t, J = 4.4 Hz, 4 H),3.66 (d, J = 4.4 Hz, 2 H), 3.34-3.52 (m, 2 H), 2.77-2.97 (m, 4 H), 2.73(s, 4 H), 2.49 (s, 4 H), 2.11-2.26 (m, 2 H). 55 780.39 N.D. E E (400MHz, CDCl3) δ: δ 12.64 (s, 1 H), 9.20 (s, 1 H), 8.49 (s, 1 H), 8.37 (d,J = 8.0 Hz, 1 H), 7.80 (d, J = 8.4 Hz, 1 H), 7.69 (d, J = 8.8 Hz, 1 H),7.62-7.66 (m, 4 H), 7.52-7.57 (m, 1 H), 7.48-7.52 (m, 1 H), 7.39-7.41(m, 2 H), 7.21-7.24 (m, 3 H), 4.99 (dd, J = 12.4, 5.2 Hz, 1 H), 4.26 (t,J = 5.2 Hz, 2 H), 3.62-3.71 (m, 1 H), 3.48-3.59 (m, 1 H), 2.82-2.92 (m,4 H), 2.64 (d, J = 7.2 Hz, 4 H), 2.50 (s, 4 H), 2.11- 2.20 (m, 2 H). 56810.4 N.D. E E (400 MHz, CDCl3) δ 12.67 (s, 1 H), 9.07 (s, 1 H),8.47-8.56 (m, 1 H), 8.39 (d, J = 8.0 Hz, 1 H), 7.77-7.83 (m, 1 H), 7.70(d, J = 8.0 Hz, 1 H), 7.48-7.57 (m, 2 H), 7.35-7.44 (m, 2 H), 7.20-7.26(m, 5 H), 7.05-7.12 (m, 1 H), 4.99 (dd, J = 12.4, 5.2 Hz, 1 H),4.19-4.32 (m, 2 H), 3.90 (s, 3 H), 3.63-3.73 (m, 1 H), 3.55 (d, J = 12.8Hz, 1 H), 2.74-2.96 (m, 4 H), 2.64 (d, J = 8.0 Hz, 4 H), 2.51 (s, 4 H),2.12-2.20 (m, 2 H). 57 854.43 N.D. N.D. E (400 MHz, CDCl3) δ =12.49-12.87 (m, 1 H), 9.71-9.88 (m, 1 H), 8.54 (s, 1 H), 8.43 (d, J =7.6 Hz, 1 H), 7.84 (d, J = 8.4 Hz, 1 H), 7.70 (d, J = 8.0 Hz, 1 H),7.48-7.57 (m, 2 H), 7.28- 7.43 (m, 3 H), 7.17-7.25 (m, 4 H), 7.04-7.12(m, 1 H), 4.99-5.16 (m, 1 H), 4.20-4.40 (m, 2 H), 3.84-3.95 (m, 5 H),3.66-3.77 (m, 2 H), 3.53-3.64 (m, 1 H), 3.31-3.45 (m, 1 H), 2.84-2.97(m, 2 H), 2.13-2.78 (m, 12 H). 58 764.5 B A A (400 MHz, CDCl3) δ 10.72(s, 1 H), 8.86 (s, 1 H), 8.52 (d, J = 8.0 Hz, 2 H), 8.13 (t, J = 8.0 Hz,1 H), 7.84-7.90 (m, 2 H), 7.80 (d, J = 8.4 Hz, 1 H), 7.42 (d, J = 2.4Hz, 1 H), 7.23-7.26 (m, 1 H), 7.09 (s, 1 H), 4.98 (dd, J = 12.4, 5.6 Hz,1 H), 4.42 (s, 1 H), 4.25-4.35 (m, 2 H), 4.04 (s, 3 H), 3.88-3.93 (m, 2H), 3.77 (s, 2 H), 3.21 (s, 2 H), 2.57-2.99 (m, 6 H), 2.12- 2.32 (m, 6H). 59 808.54 B D A (400 MHz, CDCl3) δ ppm δ 10.71 (s, 1 H), 8.83 (s, 1H), 8.42-8.55 (m, 2 H), 8.13 (t, J = 8.0 Hz, 1 H), 7.89 (s, 1 H), 7.86(d, J = 7.6 Hz, 1 H), 7.79 (d, J = 8.4 Hz, 1 H), 7.40 (d, J = 2.4 Hz, 1H), 7.24 (dd, J = 8.4, 2.31 Hz, 1 H), 7.07 (s, 1 H), 4.97 (dd, J = 12.4,5.2 Hz, 1 H), 4.35- 4.45 (m, 1 H), 4.24-4.32 (m, 2 H), 4.04 (s, 3 H),3.88-3.96 (m, 2 H), 3.67-3.76 (m, 6 H), 3.19 (d, J = 11.6 Hz, 2 H),2.71-2.86 (m, 4 H), 2.10-2.47 (m, 8 H). 60 750.53 B A A (400 MHz, CDCl3)δ ppm 10.98 (s, 1 H) 10.51 (s, 1 H) 8.69 (s, 1 H) 8.33-8.52 (m, 3 H)8.23 (d, J = 7.70 Hz, 1 H) 7.64 (d, J = 8.30 Hz, 1 H) 7.15-7.24 (m, 2 H)7.08 (dd, J = 8.38, 2.14 Hz, 1 H) 5.08 (dd, J = 13.34, 5.01 Hz, 1 H)4.18- 4.43 (m, 5 H) 3.99 (s, 3 H) 3.74-3.85 (m, 2 H) 3.63 (t, J = 5.76Hz, 2 H) 2.83-3.12 (m, 3 H) 2.57 (br t, J = 5.82 Hz, 3 H) 2.30-2.44 (m,2 H) 1.90-2.26 (m, 7 H) 61 794.56 N.D. E A (400 MHz, DMSO-d6) δ ppm10.97 (br s, 1 H) 10.51 (s, 1 H) 8.69 (s, 1 H) 8.33-8.51 (m, 3 H) 8.22(d, J = 7.58 Hz, 1 H) 7.63 (d, J = 8.44 Hz, 1 H) 7.13-7.22 (m, 2 H) 7.08(dd, J = 8.38, 2.14 Hz, 1 H) 5.07 (dd, J = 13.34, 5.14 Hz, 1 H)4.14-4.44 (m, 5 H) 3.98 (s, 3 H) 3.74-3.85 (m, 2 H) 3.51-3.66 (m, 6 H)2.83- 3.07 (m, 3 H) 2.53-2.62 (m, 3 H) 2.31- 2.45 (m, 1 H) 1.91-2.24 (m,7 H) 62 807.55 N.D. N.D. A 63 817.57 A B A 64 851.59 N.D. N.D. A (400MHz, DMSO-d6) δ ppm δ 11.09 (s, 1 H), 10.50 (s, 1 H), 8.68 (s, 1 H),8.33-8.50 (m, 3 H), 8.22 (d, J = 7.2 Hz, 1 H), 7.54-7.61 (m, 1 H),7.11-7.19 (m, 2 H), 7.03 (d, J = 6.8 Hz, 1 H), 6.61 (t, J = 5.6 Hz, 1H), 5.04 (dd, J = 12.4, 4.8 Hz, 1 H), 4.35 (bt, J = 7.6 Hz, 1 H), 3.98(s, 3 H), 3.63 (t, J = 5.2 Hz, 2 H), 3.46- 3.59 (m, 12 H), 2.78-3.13 (m,4 H), 2.60 (s, 2 H), 1.92-2.23 (m, 8H). 65 859.63 N.D. N.D. N.D. 66903.66 B D A 67 442.86 A B A (400 MHz, CDCl3) δ ppm δ: 9.62 (s, 1H),7.72 (d, J = 8.4 Hz, 1H), 6.97 (d, J = 2.8 Hz, 1H), 6.89 (dd, J = 2.8,8.8 Hz, 1H), 4.27-4.22 (m, 1H), 3.84 (s, 3H), 3.80 (s, 3H), 2.29-2.07(m, 1H), 2.06-2.02 (m, 4H), 1.53-1.44 (m, 4H). 68 442.86 C D E N.D. =Not Determined *IRAK4 Dmax Ranges: A > 70 70 ≥ B > 50 50 ≥ C > 30 D ≤ 30**IRAK4 DC50 Ranges: A < 30 30 ≤ B < 100 100 ≤ C < 300 300 ≤ D < 1000 E≥ 1000 ***IRAK4 IC50 Ranges: A < 30 30 ≤ B < 100 100 ≤ C < 300 300 ≤ D <1000 E ≥ 1000

Protein Level Control

This description also provides methods for the control of protein levelswith a cell. This is based on the use of compounds as described herein,which are known to interact with a specific target protein such thatdegradation of a target protein in vivo will result in the control ofthe amount of protein in a biological system, preferably to a particulartherapeutic benefit.

The following examples are used to assist in describing the presentinvention, but should not be seen as limiting the present invention inany way.

Specific Embodiments of the Present Disclosure

The present disclosure encompasses the following specific embodiments.These following embodiments may include all of the features recited in aproceeding embodiment, as specified. Where applicable, the followingembodiments may also include the features recited in any proceedingembodiment inclusively or in the alternative.

In certain embodiments, the description provides the following exemplaryIRAK PROTAC molecules, including salts, prodrugs, polymorphs, analogs,derivatives, and deuterated forms thereof.

In certain other embodiments, the bifunctional compounds is selectedfrom exemplary compounds 1-14 and 25-68.

In certain other embodiments, the description provides exemplary IRAKPROTAC molecules by selecting a PTM from Table 6 (e.g., a PTM selectedfrom the group consisting of PTM1 through PTM91), a linker from Table 7(e.g., a linker selected from the group consisting of Linker1 throughLinker18), and a ULM from Table 8 (e.g., a linker selected from thegroup consisting of ULM1 through ULM25), including salts, prodrugs,polymorphs, analogs, derivatives, and deuterated forms thereof:

TABLE 6 Exemplary PTMs PTM Number Chemical Structure PTM1 

PTM2 

PTM3 

PTM4 

PTM5 

PTM6 

PTM7 

PTM8 

PTM9 

PTM10

PTM11

PTM12

PTM13

PTM14

PTM15

PTM16

PTM17

PTM18

PTM19

PTM20

PTM21

PTM22

PTM23

PTM24

PTM25

PTM26

PTM27

PTM33

PTM28

PTM34

PTM29

PTM35

PTM30

PTM36

PTM31

PTM37

PTM32

PTM38

PTM39

PTM40

PTM41

PTM42

PTM43

PTM44

PTM45

PTM46

PTM47

PTM48

PTM49

PTM50

PTM51

PTM52

PTM53

PTM54

PTM55

PTM56

PTM57

PTM58

PTM59

PTM60

PTM61

PTM62

PTM63

PTM64

PTM65

PTM66

PTM67

PTM68

PTM69

PTM70

PTM71

PTM72

PTM73

PTM74

PTM75

PTM76

PTM77

PTM78

PTM79

PTM80

PTM81

PTM82

PTM83

PTM84

PTM85

PTM86

PTM87

PTM88

PTM89

PTM90

PTM91

TABLE 7 Exemplary Linkers Linker Number Chemical Structure Linker1 

Linker2 

Linker3 

Linker4 

Linker5 

Linker6 

Linker7 

Linker8 

Linker9 

Linker10

Linker 11

Linker 12

Linker 13

Linker 14

Linker 15

Linker 16

Linker 17

Linker 18

TABLE 8 Exemplary ULMs ULM Number Structure ULM1 

ULM2 

ULM3 

ULM4 

ULM5 

ULM6 

ULM7 

ULM8 

ULM9 

ULM10

ULM11

ULM12

ULM13

ULM14

ULM15

ULM16

ULM17

ULM18

ULM19

ULM20

ULM21

ULM22

ULM23

Additionally, the description provides a compound comprising a PTM fromTable 6 (i.e., a PTM selected from the group consisting of PTM1-PTM91),a linker from Table 7 (i.e., a linker selected from the group consistingof Linker1-Linker18), and a ULM from Table 8 (i.e., a ULM selected fromthe group consisting of ULM1-ULM23), including salts, prodrugs,polymorphs, analogs, derivatives, and deuterated forms thereof.

In other embodiments, the description provides a composition comprisinga compound having a PTM from Table 6 (i.e., a PTM selected from thegroup consisting of PTM1-PTM91), a linker from Table 7 (i.e., a linkerselected from the group consisting of Linker1-Linker18), and a ULM fromTable 8 (i.e., a ULM selected from the group consisting of ULM1-ULM23),including salts, prodrugs, polymorphs, analogs, derivatives, anddeuterated forms thereof.

In an aspect, the present disclosure provides a bifunctional compoundhaving the chemical structure:

ULM-L-PTM,

or a pharmaceutically acceptable salt, enantiomer, stereoisomer,solvate, polymorph or prodrug thereof, wherein: the ULM is a smallmolecule E3 ubiquitin ligase binding moiety that binds an E3 ubiquitinligase; the PTM is a small molecule comprising an Interleukin-1Receptor-Associated Kinase 4 (IRAK-4) targeting moiety; and the L is abond or a chemical linking moiety connecting the ULM and the PTM.

In any aspect or embodiment described herein, at least one of: the PTMis selected from Table 6, the linker (L) is selected from Table 7, theULM is selected from Table 8, or a combination thereof.

In any aspect or embodiment described herein, the E3 ubiquitin ligasebinding moiety that targets an E3 ubiquitin ligase selected from thegroup consisting of Von Hippel-Lindau (VLM), cereblon (CLM), mousedouble-minute homolog2 (MLM), and IAP (ILM).

In any aspect or embodiment described herein, the PTM is represented byFormula PTM-I:

wherein:

-   -   X of PTM-I is —N═ or —CH═;    -   Y of PTM-I is selected from the group consisting of —NR²⁻, —CH₂—        and —O—; or when Y is —NR²—, R² and R³ together with the        nitrogen to which they are attached optionally form a 4- to        6-membered heterocyclic ring, wherein the 4- to 6-membered        heterocyclic ring is optionally substituted with 1 to 3        substituents independently selected from R⁷ groups;    -   R¹ of PTM-I is selected from the group consisting of: hydrogen,        C₁₋₁₀ alkyl, C₃₋₈ cycloalkyl, aryl, heterocyclyl, halogen,        —COOR⁷, —NR⁷, —SR⁷, —OR⁷, —SO₂R⁷, —COR, —NCOR⁷, and —CONR⁷;    -   R² of PTM-I is selected from the group consisting of: hydrogen,        C₁₋₁₀ alkyl, and C₃₋₄ cycloalkyl;    -   R³ of PTM-I is selected from the group consisting of: hydrogen,        C₁₋₁₀ alkyl, C₃₋₄ cycloalkyl, aryl, heterocyclyl, and —COOR⁷;    -   R⁶ of PTM-I is selected from the group consisting of: C₁₋₁₀        alkyl, C₃₋₄ cycloalkyl, aryl, heterocyclyl, —COOR⁷, —SO₂R⁷,        —COR⁷; and    -   R⁷ of PTM-I is selected from the group consisting of: hydrogen,        C₁₋₁₀ alkyl, C₃₋₄ cycloalkyl, aryl, and heteroaryl;    -   wherein each of the C₁₋₁₀ alkyl, C₃₋₄ cycloalkyl, aryl and        heterocyclyl of R¹, R³, R⁶ and R⁷ is optionally substituted with        1-4 substituents independently selected from the group        consisting of C₁₋₄ alkyl, C₁₋₄ alkoxy, halogen, —SO₂R⁸ and —OR⁸;    -   R⁸ of PTM-I is selected from the group consisting of hydrogen,        and C₁₋₆ alkyl; and    -   the PTM-I is covalently joined to a ULM, a chemical linker group        (L), a CLM, an ILM, a VLM, MLM, a ULM′, a CLM′, a ILM′, a VLM′,        a MLM′, or combination thereof.

In any aspect or embodiment described herein, the PTM is represented byFormula PTM-II:

wherein:

-   -   R¹ of PTM-II is aryl, heteroaryl, heterocyclyl or (C₁₋₆        alkyl)R⁶, wherein said aryl, heteroaryl, and heterocyclyl groups        are optionally substituted with one or two substituents selected        from the group consisting of halo, cyano, R⁴, C₁₋₃ aminoalkyl,        C₁₋₃ hydroxyalkyl, C₃₋₄ cycloalkyl, OR⁴, NR⁴R⁵, NR⁴COR⁶,        NR⁴SO₂R⁶, SO₂NR⁴R⁵, CONR⁴R⁵;    -   R² of PTM-II of PTM-II is aryl, heteroaryl, C₃₋₈ cycloalkyl,        heterocyclyl or (C₁₋₆ alkyl)R⁶, wherein said aryl, heteroaryl,        cycloalkyl and heterocyclyl groups are optionally substituted        with one or two substituents selected from the group consisting        of halo, cyano, oxo, hydroxyl, imino, hydroxyimino, R⁴, OR⁴,        O(C₃₋₈ cycloalkyl), (C═O)OR⁴, SO_(m)R⁶, SO_(m)R⁴, NR⁴R⁵,        SO₂NR⁴R⁵ and NR⁴SO₂R⁶;    -   R³ of PTM-II is a halo, cyano, oxo, hydroxyl, imino,        hydroxyimino, R⁴, OR⁴, C₃₋₈ cycloalkyl, SO_(m)R⁶, SO_(m)R⁴NR⁴R⁵,        or (C═O)NR⁴R⁵, NR⁴(CO)R⁶, SO_(m)NR⁴R⁵ and NR⁴SO₂R⁶;    -   R⁴ of PTM-II is independently hydrogen or C₁₋₆ alkyl, wherein        said alkyl is optionally substituted with one to three halo or        hydroxyl;    -   R⁵ of PTM-II is independently hydrogen or C₁₋₆ alkyl, wherein        said alkyl is optionally substituted with halo or hydroxyl;    -   R⁶ of PTM-II is independently aryl, heteroaryl, C₃₋₈ cycloalkyl        or heterocyclyl; m of PTM-II is an integer from zero to two; and    -   the PTM-II is covalently joined to a ULM, a chemical linker        group (L), a CLM, an ILM, a VLM, MLM, a ULM′, a CLM′, a ILM′, a        VLM′, a MLM′, or combination thereof.

In any aspect or embodiment described herein, the PTM is represented byFormula PTM-III:

wherein:

-   -   R¹ of PTM-III is an optionally substituted aromatic heterocyclic        group or an optionally substituted C₆₋₁₄ aryl group;    -   R² of PTM-III is a hydrogen atom or a substituent;    -   R³ and R⁴ of PTM-III are independently a hydrogen atom or a        substituent, or R³ and R⁴ in combination optionally form an        optionally substituted ring;    -   R⁵ and R⁶ of PTM-III are independently a hydrogen atom or a        substituent, or R⁵ and R⁶ in combination optionally form an        optionally substituted ring;    -   X of PTM-III is CR⁷R⁸, NR⁹, O or S;    -   R⁷ and R⁸ of PTM-III are independently a hydrogen atom or a        substituent, or R⁷ and R⁸ in combination optionally form an        optionally substituted ring;    -   R⁹ of PTM-III is a hydrogen atom or a substituent; and    -   the PTM-III is covalently joined to a ULM, a chemical linker        group (L), a CLM, an ILM, a VLM, MLM, a ULM′, a CLM′, a ILM′, a        VLM′, a MLM′, or combination thereof

In any aspect or embodiment described herein, the PTM is represented byFormula PTM-IV:

wherein:

-   -   HET of PTM-IV is a heteroaryl selected from pyrazolyl, indolyl,        pyrrolo[2,3-b]pyridinyl, pyrrolo[2,3-d]pyrimidinyl,        pyrazolo[3,4-b]pyridinyl, pyrazolo[3,4-d]pyrimidinyl,        2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, imidazo[4,5-b]pyridinyl,        and purinyl, wherein said heteroaryl is substituted with R_(a)        and R_(b);    -   R_(a) of PTM-IV is H, F, Cl, Br, —CN, —OH, C₁₋₄ alkyl, C₁₋₄        fluoroalkyl, C₁₋₄ hydroxyalkyl, C₁₋₄ alkoxy, —NH₂, —NH(C₁₋₄        alkyl), —N(C₁₋₄ alkyl)₂, —NH(C₁₋₄ hydroxyalkyl), NH(C₁₋₄        fluoroalkyl), —NH(C₁₋₆ hydroxy-fluoroalkyl), —C(O)NH₂,        —CH₂NHC(O)(C₁₋₆ alkyl), —CH₂NHC(O)(C₁₋₆ hydroxyalkyl),        —CH₂NHC(O)NH(C₁₋₆ alkyl), CH₂NHC(O)NHCH₂(phenyl),        —CH₂NHC(O)N(C₁₋₄ alkyl)₂, —CH₂NHC(O)O(C₁₋₄ alkyl),        —CH₂NHC(O)(C₃₋₆ cycloalkyl), —CH₂NHC(O)(tetrahydrofuranyl),        CH₂NHC(O)CH₂(C₃₋₆ cycloalkyl), —CH₂NHC(O)CH₂(tetrahydropyranyl),        CH₂NHC(O)CH₂(phenyl), —NHC(O)(C₁₋₄ alkyl), pyrrolidinyl,        hydroxypyrrolidinyl, or pyridazinyl;    -   R_(b) of PTM-IV is H or —NH₂;    -   R₁ of PTM-IV is: (i) C₁₋₆ alkyl, C₁₋₆ fluoroalkyl, C₁₋₆        hydroxyalkyl, C₁₋₈ hydroxy-fluoroalkyl, —(C₁₋₆ alkylenyl)O(C₁₋₄        alkyl), —(C₁₋₆ alkylenyl)O(C₁₋₄ fluoroalkyl), —(C₁₋₆        fluoroalkylenyl)O(C₁₋₄ alkyl), —(C₁₋₆ fluoroalkylenyl)O(C₁₋₄        deuteroalkyl), —(C₁₋₆ fluoroalkylenyl)O(C₁₋₄ fluoroalkyl),        —(C₁₋₄ fluoroalkylenyl)C(C₃₋₆ cycloalkyl)₂(OH), (C₁₋₄        alkylenyl)NHC(O)(C₁₋₄ alkylenyl)OC(O)(C₁₋₃ alkyl), —(C₁₋₆        alkylenyl)NHS(O)₂(C₁₋₄ alkyl), —(C₁₋₆ alkylenyl)_(P)(O)(C₁₋₄        alkoxy)₂, —(C₁₋₆ fluoroalkylenyl)NH(C₁₋₄ alkyl), (C₁₋₆        alkylenyl)C(O)NH(C₁₋₄ alkyl), —(C₁₋₆ fluoroalkylenyl)C(O)NH(C₁₋₄        alkyl), —(C₁₋₆ fluoroalkylenyl)C(O)NH(C₁₋₄ hydroxyalkyl), or        —(C₁₋₆ fluoroalkylenyl)OP(O)(OH)₂; (ii) —(C₁₋₃ alkylenyl)R_(x),        —(C₁₋₃ fluoroalkylenyl)R_(x), —(C₁₋₃ alkylenyl)C(O)R_(x), —(C₁₋₃        alkylenyl)C(O)NHR_(x), —(C₁₋₃ fluoroalkylenyl)C(O)R_(x), or        —CH₂CF=(tetrahydropyranyl), wherein R_(x) is a cyclic group        selected from C₃₋₆ cycloalkyl, tetrazolyl,        1,1-dioxidotetrahydrothiophenyl, 1,1-dioxidothiomorpholinyl,        oxadiazolyl, piperidinyl, piperazinyl, pyrrolidinyl, oxetanyl,        tetrahydrofuranyl, tetrahydropyranyl, pyridinyl, imidazolyl,        morpholinyl, phenyl, and triazinyl, wherein each cyclic group is        substituted with zero to 3 substituents independently selected        from F, —OH, —CH₃, —C(CH₂)₂OH, —OCH₃, —C(O)CH₂CN, —S(O)₂CH₃,        —S(O)₂NH₂, —NHC(O)CH₃, —N(S(O)₂CH₃)₂, —CH₂CH₂(acetamidophenyl),        —CH₂CH₂(methoxyphenyl), —CH₂CH₂ (sulfamoylphenyl), oxetanyl,        benzyl, and morpholinyl; (iii) C3-6 cycloalkyl or C4-6        cycloalkenyl, each substituted with zero to 3 substituents        independently selected from F, —OH, —CN, C1-3 alkyl, C1-3        alkoxy, —S(C1-3 alkyl), —NO2, —S(O)2(C1-3 alkyl), C1-4        hydroxyalkyl, —C(C1-3 alkyl)(OH)(C3-6 cycloalkyl),        —CH2C(O)NH(C1-3 alkyl), —NHC(O)(C1-3 alkyl), —NHC(O)(C1-4        hydroxyalkyl), —C(O)NH(C1-3 alkyl), C(O)NH(C1-3 deuteroalkyl),        —C(O)NH(C3-6 cycloalkyl), —NHC(O)O(C1-3 alkyl), NHS(O)2(C1-3        alkyl), pyridinyl, imidazolyl, pyrazolyl, methylimidazolyl,        methylpyrazolyl, and thiazolyl; (iv) tetrahydropyranyl,        piperidinyl, pyrazolyl, phenyl, pyridinyl, or pyrimidinyl, each        substituted with zero to 1 substituent selected from —OH, C1-3        alkyl, C1-3 fluoroalkyl, C1-4 hydroxyalkyl, C1-3 alkoxy,        —C(O)(C1-4 alkyl), S(O)2(C1-4 alkyl), —S(O)2NH(C1-4 alkyl),        —NH(C1-3 alkyl), —N(C1-3 alkyl)2, O(C1-3 alkylenyl)N(C1-3        alkyl)2, —CH2(morpholinyl), azetidinyl, oxetanyl,        tetrahydropyranyl, morpholinyl, piperazinyl, piperidinyl,        methylpiperazinyl, methoxypiperidinyl, pyridinyl, pyrimidinyl,        methylsulfonyl azetidinyl, and C(O)(methylsulfonyl azetidinyl);        or (v) pyrrolo[2,3-c]pyridinyl, bicyclo[2.2.1]heptan-1-ol,        tetrahydrobenzo[d]thiazol-2-amine, or        1,3-diazaspiro[4.5]decane-2,4-dione;    -   R₂ of PTM-IV is: (i) C₁₋₇ alkyl or C₂₋₆ alkenyl, each        substituted with zero to three substituents independently        selected from F, —OH, and —CN; —(C₁₋₄ alkylenyl)O(C₁₋₄ alkyl),        —(C₁₋₄ alkylenyl)O(C₁₋₄ fluoroalkyl), —(C₁₋₆ alkylenyl)NH2,        —(C₁₋₆ alkylenyl)S(O)₂(C₁₋₃ alkyl), —(C₁₋₆        fluoroalkylenyl)NH(C₁₋₃ alkyl), or —(C₁₋₆ alkylenyl)NHC(O)(C₁₋₄        fluoroalkyl); (ii) —(C₁₋₄ alkylenyl)R_(y) wherein R_(y) is C₃₋₆        cycloalkyl, azetidinyl, oxetanyl, oxazolyl, pyridinyl,        tetrahydropyranyl, or morpholinyl, each substituted with zero to        2 substituents independently selected from F, —OH, and C₁₋₃        alkyl; (iii) C₃₋₆ cycloalkyl, azetidinyl, oxetanyl, furanyl,        tetrahydrofuranyl, pyrrolidinyl, piperidinyl, or        tetrahydropyranyl, each substituted with zero to 3 substituents        independently selected from F, —OH, C₁₋₃ alkyl, C₁₋₃        hydroxyalkyl, —C(O)(C₁₋₃ alkyl), —C(O)(C₁₋₃ fluoroalkyl),        —C(O)(C₁₋₃ cyanoalkyl), —C(O)O(C₁₋₃ alkyl), —C(O)NH₂,        —C(O)NH(C₁₋₃ alkyl), —C(O)(difluorophenyl), NH₂, —NH(C₁₋₃        alkyl), —NH(C₁₋₃ fluoroalkyl), —NH(oxetanyl), —NHC(O)(C₁₋₃        alkyl), —NHC(O)(C₁₋₃ fluoroalkyl), —NHC(O)(C₃₋₆ cycloalkyl),        —NHC(O)(fluorophenyl), —S(O)₂(C₁₋₃ alkyl), imidazolyl, phenyl,        pyrimidinyl, fluoropyrimidinyl, chloropyrimidinyl, and        methoxypyrimidinyl; (iv) adamantanyl, hydroxyadamantanyl,        benzo[d]imidazolyl, benzo[d]oxazolyl, benzo[d]triazolyl,        benzothiazolyl, bicyclo[1.1.1]pentanyl, or        hydroxybicyclo[2.2.1]heptanyl; or (v) phenyl, pyrazolyl,        thiazolyl, thiadiazolyl, or indazolyl, each substituted with 0        to 2 substituents independently selected from F, Cl, —OH, —CN,        C₁₋₄ alkyl, C₁₋₄ hydroxyalkyl, C₁₋₄ fluoroalkyl, C₁₋₄        cyanoalkyl, C₁₋₃ alkoxy, C₃₋₆ cycloalkyl, (C₁₋₃ alkylenyl)O(C₁₋₃        alkyl), —(C₁₋₃ alkylenyl)O(C₁₋₃ fluoroalkyl), —C(O)NH₂,        C(O)NH(C₁₋₃ alkyl), —NHC(O)(C₁₋₃ alkyl), —NHC(O)S(O)₂(C₁₋₃        alkyl), —S(O)₂NH₂, —S(O)₂(C₁₋₃ alkyl), pyrazolyl, methyl        pyrazolyl, imidazolyl, triazolyl, methyl tetrazolyl, ethyl        tetrazolyl, phenyl, pyrimidinyl, fluoropyrimidinyl, and        tetrahydropyranyl; and    -   the PTM-IV is covalently joined to a ULM, a chemical linker        group (L), a CLM, an ILM, a VLM, MLM, a ULM′, a CLM′, a ILM′, a        VLM′, a MLM′, or combination thereof.

In any aspect or embodiment described herein, the PTM is represented byFormula PTM-Va or PTM-Vb:

wherein:

-   -   X₁ and X₃ of PTM-Va or PTM-Vb independently are CH or N; X₂ of        PTM-V is CR₂ or N; provided one and not more than one of X₁, X₂        or X₃ is N;    -   Y of PTM-Va or PTM-Vb is —CH₂— or O;    -   Ring Z of PTM-Va or PTM-Vb is aryl, heteroaryl, or heterocyclyl;    -   A of PTM-Va or PTM-Vb is O, S, or NH;    -   R₁ of PTM-Va or PTM-Vb at each occurrence, is independently        hydrogen, cyano, halo, hydroxy, —NO2, —NR₅R₆, optionally        substituted alkyl, optionally substituted aryl, optionally        substituted cycloalkyl, optionally substituted heterocycloalkyl,        optionally substituted heterocyclyl or optionally substituted        heteroaryl, wherein the substituent, in each occurrence, is        independently selected from alkyl, alkoxy, haloalkyl, cyano,        aminoalkyl, halo, hydroxyl, hydroxyalkyl, —NR⁷R⁸, or COOR⁹;    -   R₂ of PTM-Va or PTM-Vb is hydrogen, optionally substituted        cycloalkyl, optionally substituted aryl, optionally substituted        heterocyclyl or —NR_(a)R_(b); wherein the substituent is alkyl,        amino, halo or hydroxyl;    -   R₃ of PTM-Va or PTM-Vb, at each occurrence, is independently        selected from hydrogen, carboxy, cyano, hydroxy, hydroxyalkyl,        alkyl, aryl, heteroaryl, —SO₂R⁷, hydroxyl or oxo;    -   R₄ of PTM-Va or PTM-Vb at each occurence is independently        selected from hydrogen, halogen, alkyl, aryl, heterocycloalkyi,        heterocycloalkylalkyl, heteroaryl, Y-arylalkyl or —Y-cycloalkyl;        wherein cycloalkyl, aryl, heterocycloalkyi,        heterocycloalkylalkyl, heteroaryl and arylalkyl can be        optionally substituted with hydroxy, alkyl, haloalkyl, cyano or        halo; Y₁ of PTM-Va or PTM-Vb is selected from direct bond, O,        —C(O)— or NR⁹;    -   R₅ and R₆ of PTM-Va or PTM-Vb are independently selected from        hydrogen, hydroxyalkyl, aminoalkyl, acyl, optionally substituted        alkyl, optionally substituted heterocyclyl, optionally        substituted aryl; wherein the optional substituent, in each        occurrence, is independently selected from halo, haloalkyl or        —COOR₉;    -   R₇ and R⁸ of PTM-Va or PTM-Vb are independently hydrogen, alkyl,        acyl, heterocyclyl, —COR₉ or —COOR₉;    -   R₉ of PTM-Va or PTM-Vb at each occurence is independently        selected from hydrogen or alkyl;    -   R_(9a) of PTM-Vb is selected from hydrogen, halo, optionally        substituted alkoxy (e.g., optionally substituted C₁-C₄ alkoxy),        optionally substituted alkyl (e.g., C₁-C₄ alkyl optionally        substituted with halo or hydroxy), hydroxyalkyl (e.g. C₁-C₄        hydroxyalkyl), or haloalkyl (e.g., C₁-C₄ haloalkyl);    -   “m”, “n” and “q” of PTM-Va or PTM-Vb are independently selected        from 0, 1, 2, or 3;    -   “p” of PTM-Va or PTM-Vb is 0 or 1;    -   the PTM-Va or PTM-Vb is covalently joined to a ULM, a chemical        linker group (L), a CLM, an ILM, a VLM, MLM, a ULM′, a CLM′, a        ILM′, a VLM′, a MLM′, or combination thereof.

In any aspect or embodiment described herein, the PTM is represented byFormula PTM-VIa, PTM-VIb, or PTM-VIc:

wherein:

-   -   X of PTM-VIa-c is CH or N;    -   a of PTM-VIa-c is 0 or 1;    -   b of PTM-VIa-c is 0 or 1;    -   m of PTM-VIa-c is 0, 1 or 2;    -   Ring A of PTM-VIa-c is (C₃-C₅)cycloalkyl, (C₃-C₅)cycloalkenyl,        aryl or heterocycle optionally substituted with one to three        substituents independently selected from R₁;    -   R₁ of PTM-VIa-c is selected from: H, oxo,        (C═O)_(a)O_(b)(C₁-C₁₀)alkyl, (C═O)_(a)O_(b)-aryl,        (C═O)_(a)O_(b)(C₂-C₁₀)alkenyl, (C═O)_(a)O_(b)(C₂-C₁₀)alkynyl,        CO₂H, halo, OH, O_(b)(C₁-C₆)fluoroalkyl, (C═O)_(a)NR₅R⁶, CN,        (C═O)_(a)O_(b)(C₃-C₈)cycloalkyl, S(O)_(m)NR₅R₆, SH,        S(O)_(m)—(C₁-C₁₀)alkyl and (C═O)_(a)O_(b)-heterocyclyl, said        alkyl, aryl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl are        optionally substituted with one or more substituents selected        from R_(a);    -   R₂ and R₃ of PTM-VIa-c are independently selected from: H,        (C═O)_(a)O_(b)C₁-C₁₀ alkyl, (C═O)_(a)O_(b)aryl, C₂-C₁₀ alkenyl,        C₂-C₁₀ alkynyl, (C═O)_(a)O_(b) heterocyclyl, CO₂H, CN,        O_(b)C1-C₆ fluoroalkyl, O_(a)(C═O)_(b)NR₅R₆, CHO, (N═O)R₅R⁶,        S(O)_(m)NR₅R₆, SH, S(O)_(m) (C₁-C₁₀)alkyl, (C═O)_(a)O_(b)C3-C₈        cycloalkyl, optionally substituted with one or more substituents        selected from R₁; or R₂ and R₃ can be taken together with the        nitrogen to which they are attached to form a monocyclic or        bicyclic heterocycle with 3-7 members in each ring and        optionally containing, in addition to the nitrogen, one or two        additional heteroatoms selected from N, O and S, said monocyclic        or bicyclic heterocycle optionally substituted with one or more        substituents selected from R₁;    -   R₄ of PTM-VIa-c is selected from: (C₁-C₆)alkyl and        (C₃-C₆)cycloalkyl, optionally substituted with R_(a);    -   R₅ and R₆ of PTM-VIa-c are independently selected from: H, oxo,        (C═O)_(a)O_(b)(C₁-C₁₀)alkyl, (C═O)_(a)O_(b)-aryl,        (C═O)_(a)O_(b)(C₂-C₁₀)alkenyl, (C═O)_(a)O_(b)(C₂-C₁₀)alkynyl,        CO₂H, O_(b)(C₁-C₆)fluoroalkyl, (C═O)_(a)N(R_(a))₂, CN,        (C═O)_(a)O_(b)(C₃-C₈)cycloalkyl, S(O)_(m) N(R_(a))₂, SH,        S(O)_(m)—(C₁-C₁₀)alkyl and (C═O)_(a)O_(b)-heterocyclyl, said        alkyl, aryl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl are        optionally substituted with one or more substituents selected        from R_(a);    -   R_(a) of PTM-VIa-c is independently selected from R_(b), OH,        (C₁-C₆)alkoxy, halogen, cyclopropyl, CO₂H, CN,        O_(a)(C═O)_(b)(C₁-C₆)alkyl, oxo, and N(R^(b))₂;    -   R_(b) of PTM-VIa-c is independently selected from H and        (C₁-C₆)alkyl; and    -   the PTM-Via-c is covalently joined to a ULM, a chemical linker        group (L), a CLM, an ILM, a VLM, MLM, a ULM′, a CLM′, a ILM′, a        VLM′, a MLM′, or combination thereof.

In any aspect or embodiment described herein, the PTM is represented byFormula PTM-VIIa, PTM-VIIb, PTM-VIIc, PTM-VIId, PTM-VIIe, PTM-VIIf,PTM-VIIg, PTM-VIIh, PTM-VIIi, PTM-VIIj, PTM-VIIk, or PTM-VIIm:

wherein:

-   -   X and X′ of PTM-VIIa-k or PTM-VIIm are each independently CR⁸, N        or —N⁺—O—; Y is independently N, —N⁺—O⁻ or CR^(8′); provided        that at least one of X, X′ or Y is neither N nor —N⁺—O⁻ and that        no more than one of X, X′ or Y is —N⁺—O—;    -   R¹ of PTM-VIIa-k or PTM-VIIm is C₁-C₆alkyl; C₂-C₆alkenyl;        C₂-C₆alkynyl; —(CR^(3a)R^(3b))_(m)-(3- to 7-membered        cycloalkyl); —(CR^(3a)R^(3b))_(m)-(3- to 7-membered        heterocycloalkyl) having one to three heteroatoms;        —(CR^(3a)R^(3b))_(m)-(5- to 10-membered heteroaryl), having one        to three heteroatoms; or —(CR^(3a)R^(3b))_(m)—C₆-C₁₂aryl;        wherein said alkyl, alkenyl, alkynyl, cycloalkyl,        heterocycloalkyl, heteroaryl or aryl is optionally substituted        with one to five halogen, deuterium, —OR⁵, —SR⁵,        —NR^(11a)R^(11b), cyano, C₁-C₆alkyl, C₃-C₆cycloalkyl or        —C₁-C₆alkoxy;    -   R² of PTM-VIIa-k or PTM-VIIm is —(CR^(3a)R^(3b))_(m)-(3- to        10-membered cycloalkyl); (CR^(3a)R^(3b))_(m)-(3- to 10-membered        heterocycloalkyl) having one to three heteroatoms;        —(CR^(3a)R^(3b))_(m)-(5- to 10 membered heteroaryl) having one        to three heteroatoms; or —(CR^(3a)R^(3b))_(m)—C₆-C₁₂aryl;        wherein said cycloalkyl, heterocycloalkyl, heteroaryl or aryl is        optionally substituted with one to five R⁴; and wherein, if the        heteroatom on said heterocycloalkyl and heteroaryl is N, said N        is optionally substituted with R^(4′); or R² is C₁-C₆alkyl,        wherein said alkyl is optionally substituted with NH₂, OH or        cyano;    -   R^(3a) and R^(3b) of PTM-VIIa-k or PTM-VIIm for each occurrence        are independently hydrogen or C₁-C₃alkyl;    -   R⁴ of PTM-VIIa-k or PTM-VIIm for each occurrence is        independently a bond, deuterium, halogen, cyano, C₁-C₆alkyl,        C₂-C₆alkenyl, oxo, —OR⁵, —SR⁵, —S(O)R⁹, —S(O)₂R⁹,        NR^(11a)R^(11b), —C(O)R¹⁰, —(CR^(3a)R^(3b))_(n)-(3- to        7-membered cycloalkyl), —(CR^(3a)R^(3b))_(n)-(4- to 10-membered        heterocycloalkyl), having one to three heteroatoms,        —(CR^(3a)R^(3b))_(n)-(5- to 10 membered heteroaryl), having one        to three heteroatoms, or —(CR^(3a)R^(3b))_(n)-C₆-C₁₂aryl wherein        said alkyl, cycloalkyl, heterocycloalkyl, heteroaryl or aryl is        each optionally and independently substituted with one to five        deuterium, halogen, OR⁵, —SR⁵, —NR^(11a)R^(11b) cyano,        C₁-C₆alkyl, C₃-C₆cycloalkyl or C₁-C₆alkoxy; or two R⁴ taken        together with the respective carbons to which each are bonded        form a 3- to 6-membered cycloalkyl or 4- to 6-membered        heterocycloalkyl, wherein said cycloalkyl or heterocycloalkyl is        optionally substituted with one to three halogen, deuterium,        —OR⁵, —SR⁵, —NR^(11a)R^(1l)b, cyano or C₁-C₆alkyl or        C₁-C₆alkoxy, wherein the alkyl or alkoxy is optionally        substituted with halogen, deuterium, —OR⁵, —SR⁵,        —NR^(11a)R^(11b) or cyano; and wherein, if a heteroatom on said        heterocycloalkyl is N, said N is optionally substituted with        R^(4′);    -   R^(4′) of PTM-VIIa-k or PTM-VIIm is independently C₁-C₆alkyl,        C₂-C₆alkenyl, —C(O)R¹⁰, —S(O)₂R⁹, —(CR^(3a)R^(3b))_(n)-(3- to        7-membered cycloalkyl), —(CR^(3a)R^(3b))_(n)-(4- to 10-membered        heterocycloalkyl) or C(O)(CH₂)_(t)CN; wherein said alkyl,        alkenyl, cycloalkyl, or heterocycloalkyl is each optionally and        independently substituted with one to five deuterium, halogen,        OH, cyano or C₁-C₆alkoxy; or R⁴ and R^(4′) taken together with        the respective atoms to which each are bonded form a 3- to        6-membered cycloalkyl or 4- to 6-membered heterocycloalkyl,        wherein said cycloalkyl or heterocycloalkyl is optionally        substituted with one to three halogen, deuterium, —OR⁵, —SR⁵,        cyano, C₁-C₆alkyl or C₁-C₆alkoxy, wherein the alkyl or alkoxy is        optionally substituted with halogen, deuterium, —OR⁵, —SR⁵,        —NR^(11a)R^(11b), or cyano;    -   R^(4a) and R^(4b) of PTM-VIIa-k or PTM-VIIm are each        independently hydrogen, deuterium, fluoro, OH, —OR⁵, methyl,        ethyl, vinyl, cyclopropyl or propyl, optionally substituted with        one to five deuterium, fluoro, methoxy or OH;    -   R^(4c) and R^(4d) of PTM-VIIa-k or PTM-VIIm for each occurrence        are independently and optionally halogen, OH, deuterium,        C₁-C₆alkyl, C₂-C₆alkenyl, —OR⁵, —(CR^(3a)R^(3b))_(n)-(3-to        6-membered cycloalkyl), or —(CR^(3a)R^(3b))_(n)-(4- to        6-membered heterocycloalkyl) wherein said alkyl, cycloalkyl and        heterocycloalkyl are each optionally and independently        substituted with one to five deuterium, halogen, OH, cyano, or        C₁-C₆alkoxy; NH₂; or R^(4c) and R^(4d) taken together with the        carbons to which they are bonded form a 4- to 7-membered        heterocycloalkyl or a 3- to 7-membered cycloalkyl, wherein said        heterocycloalkyl or cycloalkyl is optionally substituted with        one to three fluoro, C₁-C₃alkyl or C₁-C₃fluoroalkyl;    -   or R^(4a) and R^(4c) of PTM-VIIa-k or PTM-VIIm taken together        with the carbon to which they are bonded form a 4- to 7-membered        heterocycloalkyl or a 3- to 7-membered cycloalkyl, wherein said        heterocycloalkyl or cycloalkyl is optionally substituted with        one to three fluoro, C₁-C₃alkyl or C₁-C₃fluoroalkyl;    -   R⁵ of PTM-VIIa-k or PTM-VIIm is independently hydrogen or        C₁-C₆alkyl, wherein said alkyl is optionally substituted with        halogen, deuterium, C₁-C₆alkoxy, C₁-C₆alkylthiolyl,        —NR^(11a)R^(11b), cyano, C₁-C₆alkyl or C₃-C₆cycloalkyl; or two        R⁵ taken together with the oxygen atoms to which they are bonded        form a 5- or 6-membered heterocycloalkyl;    -   R⁶ of PTM-VIIa-k or PTM-VIIm is —C(O)NHR⁷, CO₂R⁷ or cyano;    -   R⁷ of PTM-VIIa-k or PTM-VIIm is hydrogen or C₁-C₆alkyl;    -   each R⁸ of PTM-VIIa-k or PTM-VIIm is independently hydrogen,        halogen, cyano, —OR⁵, SR⁵, —C₁-C₆alkyl, C₃-C₆cycloalkyl, 3- to        10-membered heterocycloalkyl or 5- to 6-membered heteroaryl or        aryl, wherein said alkyl, cycloalkyl, heterocycloalkyl,        heteroaryl or aryl is optionally substituted with one to three        halogen, —NR^(11a)R^(11b), —OR⁵, —SR⁵, cyano, C₁-C₃ alkyl,        —C(O)R¹⁰ or oxo;    -   R^(8′) of PTM-VIIa-k or PTM-VIIm is hydrogen, deuterium,        halogen, cyano, —OR⁵, —SR⁵ or —NR^(11a)NR^(11b);    -   R⁹ of PTM-VIIa-k or PTM-VIIm is        —(CR^(3a)R^(3b))_(p)(C₁-C₃alkyl), —(CR^(3a)R^(3b))_(p)(4- to        6-membered cycloalkyl), —(CR^(3a)R^(3b))_(p)(4- to 6-membered        heterocycloalkyl) or (CR^(3a)R^(3b))_(p)(C₅-C₉aryl), wherein        said alkyl, cycloalkyl, heterocycloalkyl or aryl is each        optionally substituted with fluoro or C₁-C₃alkyl;    -   R¹⁰ of PTM-VIIa-k or PTM-VIIm is C₁-C₆alkyl, wherein said alkyl        is optionally substituted with deuterium, halogen, OH,        C₁-C₆alkoxy or cyano;    -   R^(11a) and R^(11b) of PTM-VIIa-k or PTM-VIIm are each        independently hydrogen or C₁-C₆alkyl, wherein said alkyl is        optionally substituted with deuterium, C₁-C₆alkoxy or cyano; and        if C₂-C₆alkyl, said alkyl is optionally substituted with        deuterium, C₁-C₆alkoxy, cyano, halogen or OH;    -   m of PTM-VIIa-k or PTM-VIIm is independently 0, 1, 2 or 3;    -   n of PTM-VIIa-k or PTM-VIIm is independently 0, 1, 2 or 3;    -   p of PTM-VIIa-k or PTM-VIIm is independently 0 or 1;    -   t of PTM-VIIa-k or PTM-VIIm is 1, 2 or 3; and    -   the PTM-VIIa-k is covalently joined to a ULM, a chemical linker        group (L), a CLM, an ILM, a VLM, MLM, a ULM′, a CLM′, a ILM′, a        VLM′, a MLM′, or combination thereof.

In any aspect or embodiment described herein, the PTM is represented byFormula PTM-VIIIa, PTM-VIIIb, PTM-VIIIc, PTM-VIIId, PTM-VIIIe, orPTM-VIIIf:

wherein:

-   -   Ring A of PTM-VIIIa-f is phenylene or 5- to 6-membered        heteroarylene containing 1-3 heteroatoms chosen from O, S, and        N, wherein ring A is optionally substituted with lower alkyl        that is further optionally substituted;    -   Ring B of PTM-VIIIa-f is phenylene, 5- to 6-membered        heterocycloalkylene containing 1-3 heteroatoms chosen from O, S,        and N, or 5- to 6-membered heteroarylene containing 1-3        heteroatoms chosen from O, S, and N, wherein ring B is        optionally substituted with lower alkyl or lower alkyloxyalkyl,        either of which is is further optionally substituted;    -   R² of PTM-VIIIa-f is chosen from hydrogen and lower alkyl;    -   R³ of PTM-VIIIa-f is chosen from hydrogen, lower alkyl        optionally substituted with alkoxy, amino, N— (alkyl)amino,        N,N-(dialkyl)amino, or phenyl, heterocycloalkyl, and heteroaryl,        wherein phenyl, heterocycloalkyl, and heteroaryl are optionally        substituted with one or two groups independently chosen from        lower alkyl and wherein alkoxy is optionally substituted with        tri(alkyl)silyl;    -   R⁴ of PTM-VIIIa-f is chosen from heteroarylene and arylene, each        of which is optionally substituted, or R⁴ and R³ of PTM-VIIIa-f        taken together with the nitrogen to which they are bound, form        an optionally substituted 3- to 7-membered heterocycloalkyl        ring, or R⁴ of PTM-VIIIa-f is an alkylene chain having 1-3        carbon atoms that is optionally substituted with one or two        groups independently chosen from lower alkyl and cycloalkyl,        each of which groups is optionally substituted with hydroxyl or        alkoxy, or R⁴ of PTM-VIIIa-f is absent;    -   R⁵ of PTM-VIIIa-f is chosen from C(O)NR⁵¹, NR⁵², and O, or R⁵ is        absent, provided that if R⁴ is absent, then R⁵ is absent;    -   R⁶ of PTM-VIIIa-f is an alkylene or alkenylene chain having one        or two double bonds, wherein the alkylene or alkenylene chain        has 2 to 10 carbon atoms, the alkylene or alkenylene chain is        optionally substituted with one or two groups independently        chosen from lower alkyl, cycloalkyl and phenyl, each of which        groups is optionally substituted with hydroxyl, alkoxy,        —C(O)OR⁸⁵, —C(O)NR⁸²R⁸³, benzoyl, and benzyl, further wherein        one or two of the carbon atoms in the alkylene or alkenylene        chain is optionally replaced by an O, S, SO, SO₂, C(O)NR⁵¹, or        NR⁶¹, and wherein one of the carbon atoms in the alkylene or        alkenylene chain, is optionally connected by the nitrogen atom        of C(O)NR⁵¹ or NR⁶¹ to form a 5- to 7-membered ring, which may        further be substituted with oxo, wherein two of the carbon atoms        in the alkylene or alkenylene chain, are optionally connected by        a two or three carbon atom alkylene or alkenylene chain to form        a 5- to 7-membered ring;    -   R⁷ of PTM-VIIIa-f is chosen from NR⁷¹ and O, or R⁷ is absent;    -   R²¹ of PTM-VIIIa-f is chosen from hydrogen and lower alkyl        optionally substituted with lower alkoxy, wherein lower alkoxy        is optionally substituted with tri(alkyl)silyl;    -   R⁴¹ of PTM-VIIIa-f is independently chosen from        heterocycloalkyl, lower alkyl optionally substituted with        —C(O)OR⁹, amino, N-(alkyl)amino, N,N-(dialkyl)amino, cycloalkyl,        or heterocycloalkyl, —C(O)OR⁹, hydroxyl, and —C(O)NR¹⁰R¹¹,        wherein R⁹ is chosen from hydrogen and lower alkyl, R¹⁰ and R¹¹        are independently hydrogen and lower alkyl, or R¹⁰ and R¹¹,        together with the nitrogen to which they are bound form a        heterocycloalkyl, and each lower alkyl, cycloalkyl and        heterocycloalkyl is optionally substituted with one, two, or        three groups independently chosen from —C(O)OR⁹, lower alkyl,        lower alkoxy, hydroxyl, halogen, amino, N-(alkyl)amino,        N,N-(dialkyl)amino, and heterocycloalkyl;    -   R⁵¹ of PTM-VIIIa-f is chosen from hydrogen and lower alkyl;    -   R⁵² of PTM-VIIIa-f is chosen from hydrogen, lower alkyl, and        —C(O)OR⁸¹;    -   R⁶¹ of PTM-VIIIa-f is chosen from hydrogen, lower alkyl,        —(CH₂)_(n)C(O)OR⁸¹, (CH₂)_(n)C(O)NR⁸²R⁸³, —C(O)R⁸⁴,        —C(O)(CH₂)_(p)NR⁸²C(O)OR⁸¹, —C(O)(CH₂)_(p)NR⁸²R⁸³;    -   R⁷¹ of PTM-VIIIa-f is chosen from hydrogen, lower alkyl, and        —C(O)OR⁸¹;    -   R⁸¹ of PTM-VIIIa-f is hydrogen or lower alkyl;    -   R⁸² of PTM-VIIIa-f is hydrogen or lower alkyl,    -   R⁸³ of PTM-VIIIa-f is hydrogen or lower alkyl,    -   R⁸⁴ of PTM-VIIIa-f is hydrogen, lower alkyl, C₃-C₆cycloalkyl or        tetrahydropyran, wherein the lower alkyl is optionally        substituted with hydroxy or —C(O)OR⁸¹;    -   R⁸⁵ of PTM-VIIIa-f is hydrogen, lower alkyl, or benzyl,    -   n of PTM-VIIIa-f is 0, 1, 2, or 3;    -   p of PTM-VIIIa-f is 1 or 2;    -   Z of PTM-VIIIa-f is chosen from O, S, and NR²¹; and    -   the PTM-VIIIa-f is covalently joined to a ULM, a chemical linker        group (L), a CLM, an ILM, a VLM, MLM, a ULM′, a CLM′, a ILM′, a        VLM′, a MLM′, or combination thereof.

In any aspect or embodiment described herein, the PTM is represented byFormula PTM-IXa, PTM-IXb, PTM-IXc, PTM-IXd, PTM-IXe, PTM-IXf, PTM-IXg,PTM-IXh, PTM-IXi, PTM-IXj, PTM-IXk, PTM-IXl, or PTM-IXm:

wherein:

-   -   Ring A of PTM-IXa-m is selected from phenyl and 5- or 6-membered        heteroaryl;    -   Ring B of PTM-IXa-m is selected from phenyl and 5- or 6-membered        heteroaryl;    -   Ring C of PTM-IXa-m is selected from a 5- or 6-membered        cycloalkyl or cycloheteroalkyl; Rind D of PTM-IXa-m selected        from phenyl, 5-membered aryl or heteroaryl, 6-member aryl or        heteroaryl, 5-membered cycloalkyl or cycloheteroalkyl, or        6-membered cycloalkyl or cycloheteroalkyl;    -   n of PTM-IXa-e is 0, 1, or 2;    -   p of PTM-IXa-m is 0, 1, or 2;    -   one of W and X of PTM-IXa-m is N, and the other of W and X is C;    -   Y of PTM-IXa-m is N or C—R²;    -   R¹ of PTM-IXa-m is selected from C₁₋₆alkyl, C₂₋₆alkenyl,        C₂₋₆alkynyl, C₃₋₆cycloalkyl, 3-to 6-membered saturated        heterocyclyl, halo, —CN, —C(R^(1a))═NR(OR^(1a)),        —C(R^(1a))═N(R^(1a)), —C(O)R^(1a)C(O)₂R^(1a), —C(O)N(R^(1a))₂,        —NO₂, —N(R^(1a))₂, —N(R^(1a))C(O)R^(1a), —N(R^(1a))C(O)₂R^(1a),        N(R^(1a))C(O)N(R_(a))₂, —N(R^(1a))S(O)₂R^(1a), —OR^(1a),        —OC(O)R^(1a), —OC(O)N(R^(1a))₂, —SR^(1a), —S(O)R^(1a),        S(O)₂R^(1a), —S(O)N(R^(1a))₂, and —S(O)₂N(R^(1a))₂, wherein said        C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl, and 3-to        6-membered saturated heterocyclyl are optionally substituted        with one or more R¹⁰; or two R¹ substituents, together with        their intervening atoms, form a C₅₋₇cycloalkyl or a saturated 5-        to 7-membered heterocyclic ring, wherein said C₅₋₇cycloalkyl or        a saturated 5- to 7-membered heterocyclic ring are optionally        substituted with one or more R¹⁵;    -   R^(1a) of PTM-IXa-m in each occurrence is independently selected        from H, C₁₋₆alkyl, C₂-6alkenyl, C₂₋₆alkynyl, 3- to 6-membered        monocyclic carbocyclyl, and 3- to 6-membered monocyclic        heterocyclyl wherein said C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,        3- to 6-membered monocyclic carbocyclyl, and 3- to 6-membered        monocyclic heterocyclyl in each occurrence are optionally and        independently substituted with one or more R¹⁰;    -   R¹⁰ of PTM-IXa-m in each occurrence is independently selected        from ĈaUcyl, C₂₋₆alkenyl, C₂₋₆alkynyl, 3- to 6-membered        carbocyclyl, 3-to 6-membered heterocyclyl, halo, —CN,        —C(R^(10a))═NR(OR^(10a)), —C(R^(10a))═N(R^(10a)), —C(O)R^(10a),        —C(O)₂R^(10a), —C(O)N(R^(10a))₂, —N0₂, —N(R^(10a))₂,        —N(R^(10a))C(O)R^(10a), —N(R^(10a))C(O)₂R^(10a),        —N(R^(10a))C(O)N(R^(10a))₂, —N(R^(10a))S(O)₂R^(10a), —OR^(10a),        —OC(O)R^(10a), —OC(O)N(R^(10a))₂, —SR^(10a), —S(O)R^(10a),        —S(O)₂R^(10a), —S(O)N(R^(10a))₂, and —S(O)₂N(R^(10a))₂;    -   R^(10a) of PTM-IXa-m in each occurrence is independently        selected from H and C₁₋₆alkyl, wherein said C₁₋₆alkyl is        optionally substituted with one or more halo;    -   R¹⁵ of PTM-IXa-m in each occurrence is independently selected        from C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, 3- to 6-membered        carbocyclyl, 3-to 6-membered heterocyclyl, halo, —CN,        —C(R^(15a))═NR(OR^(15a)), —C(R^(15a))═N(R^(15a)), —C(O)R^(15a),        —C(O)₂R^(15a), —C(O)N(R^(15a))₂, —NO₂, —N(R^(15a))₂,        —N(R^(15a))C(O)R^(15a), —N(R^(15a))C(O)₂R^(15a),        —N(R^(15a))C(O)N(R^(15a))₂, —N(R^(15a))S(O)₂R^(15a)—OR^(15a),        —OC(O)R^(15a), —OC(O)N(R^(15a))₂, —SR^(15a), —S(O)R^(15a),        —S(O)₂R^(15a), —S(O)N(R^(15a))₂, and —S(O)₂N(R^(15a))₂;    -   R^(15a) of PTM-IXa-m in each occurrence is independently        selected from H and C₁₋₆alkyl, wherein said C₁₋₆alkyl is        optionally substituted with one or more halo;    -   R² of PTM-IXa-m is selected from H, C₁₋₆alkyl, C₂₋₆alkenyl,        C₂₋₆alkynyl, 3- to 7-membered carbocyclyl, 3-to 7-membered        heterocyclyl, halo, —CN, —C(R^(2a))═NR(OR^(2a)),        C(R^(2a))═N(R^(2a)), —C(O)R^(2a), —C(O)₂R^(2a), —C(O)N(R^(2a))₂,        —NO₂, —N(R^(2a))₂, —N(R^(2a))C(O)R^(2a), —N(R^(2a))C(O)₂R^(2a),        —N(R^(2a))C(O)N(R^(2a))₂, —N(R^(2a))S(O)₂R^(2a), —OR^(2a),        —OC(O)R^(2a), OC(O)N(R^(2a))₂, —SR^(2a), —S(O)R^(2a),        —S(O)₂R^(2a), —S(O)N(R^(2a))₂, and —S(O)₂N(R^(2a))₂, wherein        said C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, 3-to 7-membered        carbocyclyl, and 3-7 membered heterocyclyl are optionally        substituted with one or more R²⁰;    -   R^(2a) of PTM-IXa-m in each occurrence is independently selected        from H and C₁₋₆alkyl, wherein said C₁₋₆alkyl in each occurrence        is optionally and independently substituted with one or more        R²⁰;    -   R²⁰ of PTM-IXa-m in each occurrence is independently selected        from C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₇cycloalkyl, 3-to        7-membered saturated heterocyclyl, halo, —CN,        —C(R^(20a))═NR(OR^(20a)), —C(R^(20a))═N(R^(20a)), —C(O)R^(20a),        —C(O)₂R^(20a), —C(O)N(R^(20a))₂, —NO₂, —N(R^(20a))₂,        —N(R^(20a))C(O)R^(20a), —N(R^(20a))C(O)₂R^(20a),        —N(R^(20a))C(O)N(R^(20a))₂, —N(R^(20a))S(O)₂R^(20a), —OR^(20a),        —OC(O)R^(20a), —OC(O)N(R^(20a))₂, —SR^(20a), —S(O)R^(20a),        —S(O)₂R^(20a), —S(O)N(R^(20a))₂, and —S(O)₂N(R )₂, wherein said        C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₇cycloalkyl, and 3-7        membered saturated heterocyclyl in each occurrence are        optionally and independently substituted with one or more R²⁵;    -   R^(20a) of PTM-IXa-m in each occurrence is independently        selected from H and C₁₋₆alkyl, wherein said C₁₋₆alkyl is        optionally substituted with R²⁵;    -   R²⁵ of PTM-IXa-m is selected from halo and —OR^(25a);    -   R^(25a) of PTM-IXa-m is selected from H and C₁₋₆alkyl;    -   R³ of PTM-IXa-m is selected from C₁₋₆alkyl, C₂₋₆alkenyl,        C₂₋₆alkynyl, C₃₋₆cycloalkyl, 3-to 6-membered saturated        heterocyclyl, halo, —CN, —C(R^(3a))═NR(OR^(3a)),        —C(R^(3a))═N(R^(3a)), C(O)R^(3a), —C(O)₂R^(3a), —C(O)N(R^(3a))₂,        —NO₂, —N(R^(3a))₂, —N(R^(3a))C(O)R^(3a), —N(R^(3a))C(O)₂R^(3a),        N(R^(3a))C(O)N(R^(3a))₂, —N(R^(3a))S(O)₂R^(3a), —OR^(3a),        —OC(O)R^(3a), —OC(O)N(R^(3a))₂, —SR^(3a), —S(O)R^(3a),        —S(O)₂R^(3a), —S(O)N(R^(3a))₂, and —S(O)₂N(R^(3a))₂, wherein        said C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl, and        3-to 6-membered saturated heterocyclyl are optionally        substituted with one or more R³⁰;    -   R^(3a) of PTM-IXa-m in each occurrence is independently selected        from H, C₁₋₆alkyl, 3- to 6-membered carbocyclyl, and 3- to        6-membered heterocyclyl, wherein said C₁₋₆alkyl, 3- to        6-membered carbocyclyl, and 3- to 6-membered heterocyclyl in        each occurrence are optionally and independently substituted        with one or more R³⁰;    -   R³⁰ of PTM-IXa-m in each occurrence is independently selected        from C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, 3- to 6-membered        carbocyclyl, 3-to 6-membered heterocyclyl, halo, —CN,        —C(R^(30a))═NR(OR^(30a)), —C(R^(30a))═N(R^(30a)), —C(O)R^(30a),        —C(O)₂R^(30a), —C(O)N(R^(30a))₂, —NO₂, —N(R^(30a))₂,        —N(R^(30a))C(O)R^(30a), —N(R^(30a))C(O)₂R^(30a),        —N(R^(30a))C(O)N(R^(30a))₂, —N(R^(30a))S(O)₂R^(30a), — OR^(30a),        —OC(O)R^(30a), —OC(O)N(R^(30a))₂, —SR^(30a), —S(O)R^(30a),        —S(O)₂R^(30a), —S(O)N(R^(30a))₂, and —S(O)₂N(R^(30a))₂, wherein        said C₁₋₃alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, 3-6 membered        carboyclyl, 3- to 6-membered heterocyclyl in each occurence are        optionally and independently substituted with one or more R³⁵;    -   R^(30a) of PTM-IXa-m in each occurrence is independently        selected from H and C₁₋₆alkyl, wherein said C₁₋₆alkyl is        optionally substituted with one or more R³⁵;    -   R³⁵ of PTM-IXa-m in each occurrence is independently selected        from halo and —OR^(35a);    -   R^(35a) of PTM-IXa-m in each occurrence is independently        selected from H and C₁₋₆alkyl;    -   R^(35b) of PTM-IXa-m in each occurrence is independently        selected from H, halo, optionally substituted alkoxy (e.g.,        optionally substituted C₁-C₄ alkoxy), optionally substituted        alkyl (e.g., C₁-C₄ alkyl optionally substituted with halo or        hydroxy), hydroxyalkyl (e.g. C₁-C₄ hydroxyalkyl), or haloalkyl        (e.g., C₁-C₄ haloalkyl);    -   R^(35c) of PTM-IXa-m in each occurrence is independently        selected from halo or haloalkyl (e.g., C₁-C₄ haloalkyl);    -   R⁴ of PTM-IXa-m is selected from H, halo, C₁₋₆alkyl, N(R^(4a))₂,        and —OR^(4a);    -   R^(4a) of PTM-IXa-m in each occurrence is independently selected        from H and C₁₋₆alkyl; and    -   the PTM-Ixa-m is covalently joined to a ULM, a chemical linker        group (L), a CLM, an ILM, a VLM, MLM, a ULM′, a CLM′, a ILM′, a        VLM′, a MLM′, or combination thereof.

In any aspect or embodiment described herein, the PTM is represented byFormula PTM-Xa, PTM-Xb, PTM-Xc, PTM-Xd, PTM-Xe, PTM-Xf, or PTM-Xg:

-   -   A of PTM-Xa-g is

or A of PTM-X is a triazole optionally substituted by 0-2 R

-   -   X of PTM-Xa-g is N or C—R⁷;    -   R of PTM-Xa-g is hydrogen, R¹, halogen, cyano, nitro, —OR¹,        —C(═O)—R¹, —C(═O)O—R¹, —C(═O)NR¹¹—R¹, —S(═O)₂—R¹, —NR¹¹C(═O)—R¹,        —NR¹¹C(═O)NR¹¹R¹¹, —NR¹¹C(═O)NR¹¹R¹, NR¹¹C(═O)O—R, NR¹¹S(═O)₂R¹,        —NR¹¹R¹¹, or NR¹¹R¹;    -   R¹ of PTM-Xa-g is C₁₋₆ alkyl substituted with 0-4 R^(1a), C₁₋₆        haloalkyl, C₂₋₆ alkenyl substituted with 0-3 R^(1a), C₂₋₆        alkynyl substituted with 0-3 R^(1a), C₃₋₁₀ cycloalkyl        substituted with 0-3 R^(1a), C₆₋₁₀ aryl substituted with 0-3        R^(1a), a 5-10 membered heterocycle containing 1-4 heteroatoms        selected from N, O, and S, substituted with 0-3 R^(1a), or a        5-10 membered heteroaryl containing 1-4 heteroatoms selected        from N, O, and S, substituted with 0-3 R^(1a);    -   R^(1a) of PTM-Xa-g is hydrogen, ═O, F, Cl, Br, OCF₃, CN, NO₂,        —(CH₂)_(r)OR^(b), —(CH₂)_(r)SR^(b), —(CH₂)_(r)C(O)R^(b),        —(CH₂)_(r)C(O)OR^(b), —(CH₂)_(r)OC(O)R^(b), —(CH₂)_(r)NR¹¹R¹¹,        (CH₂)_(r)C(O)NR¹¹R¹¹, —(CH₂)_(r)NR^(b)C(O)R^(c),        —(CH₂)_(r)NR^(b)C(O)OR^(c), NR^(b)C(O)NR¹¹R¹¹, S(O)_(p)NR¹¹R¹¹,        NR^(b)S(O)_(p)R^(c), —S(O)R^(c), —S(O)₂R^(c), C₁₋₆ alkyl        substituted with 0-2 R^(a), C₁₋₆ haloalkyl, —(CH₂)_(r)-3-14        membered carbocycle substituted with 0-3 R^(a), or        —(CH₂)_(r)-5-7 membered heterocycle or heteroaryl, each        comprising carbon atoms and 1-4 heteroatoms selected from N, O,        and S(O)_(p) substituted with 0-3 R^(a);    -   R² of PTM-Xa-g is C₆₋₁₀ aryl substituted with 0-4 R^(2a), a 5-10        membered heterocycle containing 1-4 heteroatoms selected from N,        O, and S, substituted with 1-4 R^(2a), or a 5-10 membered        heteroaryl containing 1-4 heteroatoms selected from N, O, and S,        substituted with 0-4 R^(2a);    -   R^(2a) of PTM-Xa-g at each occurrence is independently selected        from hydrogen, ═O, halo, OCF₃, CN, NO₂, —(CH₂)_(r)OR^(b),        —(CH₂)_(r)SR^(b), —(CH₂)_(r)C(O)R^(b), —(CH₂)_(r)C(O)OR^(b),        (CH₂)_(r)OC(O)R^(b), —(CH₂)_(r)NR¹¹R¹¹, —(CH₂)_(r)C(O)NR¹¹R¹¹,        —(CH₂)_(r)NR^(b)C(O)R^(c), (CH₂)_(r)NR^(b)C(O)OR^(c),        —NR^(b)C(O)NR¹⁰R¹¹, —S(O)_(p)NR¹¹R¹¹, —NR^(b)S(O)_(p)R^(c),        —S(O)R, —S(O)₂R^(c), C₁₋₆ alkyl substituted with 0-2 R^(a), C₁₋₆        haloalkyl, —(CH₂)_(r)-3-14 membered carbocycle substituted with        0-1 R^(a), or —(CH₂)_(r)-5-7 membered heterocycle or heteroaryl,        each comprising carbon atoms and 1-4 heteroatoms selected from        N, O, and S(O)_(p) substituted with 0-2 R^(a);    -   R³ of PTM-Xa-g is C₁₋₆alkyl substituted with 0-3 R^(3a), C₁₋₆        haloalkyl, C₂₋₆ alkenyl substituted with 0-3 R^(3a), C₂₋₆        alkynyl substituted with 0-3 R^(3a), C₃₋₁₀ cycloalkyl        substituted with 0-3 R^(3a), C₆₋₁₀ aryl substituted with 0-3        R^(3a), a 5-10 membered heterocyclyl containing 1-4 heteroatoms        selected from N, O, and S, substituted with 0-3 R^(3a) or a 5-10        membered heteroaryl containing 1-4 heteroatoms selected from N,        O, and S, substituted with 0-3 R^(3a);    -   R^(3a) of PTM-Xa-g is hydrogen, ═O, F, Cl, Br, OCF₃, CN, NO₂,        —(CH₂)_(r)OR^(b), —(CH₂)_(r)SR^(b), —(CH₂)_(r)C(O)R^(b),        —(CH₂)_(r)C(O)OR^(b), —(CH₂)_(r)OC(O)R^(b), —(CH₂)_(r)NR¹¹R¹¹,        (CH₂)_(r)C(O)NR¹¹R¹¹, —(CH₂)_(r)NR^(b)C(O)R^(c),        —(CH₂)_(r)NR^(b)C(O)OR^(c), NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹,        NR^(b)S(O)_(p)R^(c), —S(O)R^(c), —S(O)₂R^(c), C₁₋₆ alkyl        substituted with 0-2 R^(a), C₁₋₆haloalkyl, —(CH₂)_(r)-3-14        membered carbocycle substituted with 0-1 R^(a), or        —(CH₂)_(r)-5-7 membered heterocycle or heteroaryl, each        comprising carbon atoms and 1-4 heteroatoms selected from N, O,        and S(O)_(p) substituted with 0-1 R^(a);    -   R⁴ and R⁵ of PTM-Xa-g are independently selected from hydrogen,        C₁₋₄ alkyl substituted with 0-1 R^(f), (CH₂)-phenyl substituted        with 0-3 R^(d), and a —(CH₂)-5-7 membered heterocycle comprising        carbon atoms and 1-4 heteroatoms selected from N, O, and        S(O)_(p);    -   R⁶ and R⁷ of PTM-Xa-g are independently at each occurrence is        selected from hydrogen, ═O, F, Cl, Br, OCF₃, CN, NO₂,        —(CH₂)_(r)OR^(b), —(CH₂)_(r)SR^(b),        —(CH₂)_(r)C(O)R^(b)(CH₂)_(r)C(O)OR^(b), —(CH₂)_(r)OC(O)R^(b),        —(CH₂)_(r)NR¹¹R¹¹, —(CH₂)_(r)C(O)NR¹¹R¹¹,        (CH₂)_(r)NR^(b)C(O)R^(c), —(CH₂)_(r)NR^(b)C(O)OR^(c),        —NR^(b)C(O)NR¹⁰R¹¹, —S(O)_(p)NR¹¹R¹¹, NR^(b)S(O)_(p)R^(c),        —S(O)R^(c), —S(O)₂R^(c), C₁₋₆alkyl substituted with 0-2 R^(a),        C₁₋₆haloalkyl, —(CH₂)_(r)-3-14 membered carbocycle substituted        with 0-3 R^(a), or —(CH₂)_(r)-5-7 membered heterocycle or        heteroaryl, each comprising carbon atoms and 1-4 heteroatoms        selected from N, O, and S(O)_(v) substituted with 0-3 R^(a),        provided R⁶ and R⁷ are not both hydrogen;    -   R¹¹ of PTM-Xa-g at each occurrence is independently hydrogen,        R^(e), C₁₋₄ alkyl substituted with 0-1 R^(f), CH₂-phenyl        substituted with 0-3 R^(d), or —(CH₂)-5-7 membered heterocycle        or heteroaryl, each comprising carbon atoms and 1-4 heteroatoms        selected from N, O, and S(O)_(v) substituted with 0-3 R^(d); or        R¹¹ and along with another R¹¹, R¹, or R² on the same nitrogen        atom may join to form an optionally substituted heterocycle;    -   R^(a) of PTM-Xa-g is hydrogen, F, Cl, Br, OCF₃, CF₃, CHF₂, CN,        NO₂, —(CH₂)_(r)OR^(b), (CH₂)_(r)SR^(b), —(CH₂)_(r)C(O)R^(b),        —(CH₂)_(r)C(O)OR^(b), —(CH₂)_(r)OC(O)R^(b), —(CH₂)_(r)NR¹¹R¹¹,        —(CH₂)_(r)C(O)NR¹¹R¹¹, —(CH₂)_(r)NR^(b)C(O)R^(c),        —(CH₂)_(r)NR^(b)C(O)OR^(c), NR^(b)C(O)NR¹⁰R¹¹, —S(O)_(p)NR¹¹R¹¹,        —NR^(b)S(O)_(p)R^(c), —S(O)R^(c), —S(O)₂R^(c), C₁₋₆ alkyl        substituted with 0-1 R^(f), C₁₋₆ haloalkyl, —(CH₂)_(r)-3-14        membered carbocycle, or —(CH₂)_(r)-5-7 membered heterocycle or        heteroaryl, each comprising carbon atoms and 1-4 heteroatoms        selected from N, O, and S(O)_(p); or two R^(a) on adjacent or        the same carbon atom form a cyclic acetal of the formula        —O—(CH₂)_(n)—O—, or —O—CF₂—O—, wherein n is selected from 1 or        2;    -   R^(b) of PTM-Xa-g is hydrogen, R^(e) of PTM-X, C₁₋₆ alkyl        substituted with 0-2 R^(d), C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl        substituted with 0-2 R^(d), or (CH₂)_(r)-phenyl substituted with        0-3 R^(d); R^(e) is C₁₋₆ alkyl substituted with 0-1 R^(f), C₃₋₆        cycloalkyl, or (CH₂)_(r)-phenyl substituted with 0-3 R^(f);    -   R^(c) of PTM-Xa-g is C₁₋₆alkyl, C₃₋₆cycloalkyl, or        (CH₂)_(r)-phenyl substituted with 0-3 R^(f);    -   R^(d) of PTM-Xa-g is hydrogen, F, Cl, Br, OCF₃, CF₃, CN, NO₂,        —OR^(e), —(CH₂)_(r)C(O)R^(e), NR^(e)R^(e), —NR^(e)C(O)OR^(c),        C₁₋₆ alkyl, or (CH₂)_(r)-phenyl substituted with 0-3 R^(f);    -   R^(e) of PTM-Xa-g is selected from hydrogen, C₁₋₆ alkyl, C₃₋₆        cycloalkyl, and (CH₂)_(r)-phenyl substituted with 0-3 R^(f);    -   R^(f) of PTM-Xa-g is hydrogen, halo, NH₂, OH, or O(C₁₋₆alkyl);    -   p of PTM-Xa-g is 0, 1, or 2;    -   r of PTM-Xa-g is 0, 1, 2, 3, or 4;    -   m of PTM-Xa-g is 0, 1, or 2; and    -   the PTM-Xa-g is covalently joined to a ULM, a chemical linker        group (L), a CLM, an ILM, a VLM, MLM, a ULM′, a CLM′, a ILM′, a        VLM′, a MLM′, or combination thereof.

In any aspect or embodiment described herein, the PTM is represented byFormula PTM-XIa, PTM-XIb, or PTM-XIc:

wherein:

-   -   X of PTM-XIa-c is NH or O;    -   b of PTM-XIa-c is 0 or 1;    -   n of PTM-XIa-c is 0, 1, 2, 3 or 4;    -   R₁ and R₂ of PTM-XIa-c are independently H, (C₁-C₄)alkyl and        heterocyclyl, or R₁ and R₂ can be taken together with the        nitrogen to which they are attached to form a monocyclic or        bicyclic (fused, bridged or spirocyclic) heterocycle containing        3-8 carbon atoms optionally containing, in addition to the        nitrogen, one or two additional heteroatoms selected from N, O        and S, said alkyl and heterocycle are optionally substituted        with one or more substituents selected from R_(a);    -   R³ of PTM-XIa-c is (C₁-C₄)alkyl wherein two adjacent alkyl        groups can join together and form a bridged moiety of 3-6 carbon        atoms;    -   R₄ of PTM-XIa-c is absent, halo or O_(b)(C₁-C₄)alkyl;    -   R₅ of PTM-XIa-c is selected from halo, CN, O(C₁-C₄)alkyl, C₁-C₄        alkyl and C₂-C₄ alkenyl which are optionally substituted with        one or more substituents selected from R^(b) or R₅ is aryl or        heteroaryl each optionally substituted with one or more        substitutents selected from R^(b);    -   R₆ of PTM-XIa-c is absent, halo, or O(C₁-C₄)alkyl;    -   R_(a) of PTM-XIa-c is halo, oxo, OH, O_(b)(C₁-C₄)alkyl,        C(O)O_(b)(C₁-C₆)alkyl, (C═O)_(b)heterocyclyl, SO₂H, CF₃,        SO₂(C₁-C₄)alkyl, C(O)C₁-C₄alkyl, or heterocyclyl, wherein said        alkyl can come together with another alkyl to form a bridged        moiety and said alkyl and heterocyclyl are optionally        substituted with one or more substituents independently selected        from F and (C₁-C₄)alkyl; and    -   R_(b) of PTM-XIa-c is independently selected from OH, halo,        CHF₂, CF₃, COOH, SO₂(C₁-C₄)alkyl, C(O)C₁-C₄alkyl, (C═O)NH₂,        O_(b)(C₁-C₄)alkyl, aryl, heterocyclyl, CN, C(O)N(R^(c))₂,        N(R^(c))₂, wherein the R^(C) and alkyl are optionally        substituted with OH, O(C₁-C₄)alkyl and heterocyclyl;    -   R_(c) of PTM-XIa-c is independently selected from H,        SO₂(C₁-C₄)alkyl, or C₁-C₄ alkyl;    -   the PTM-XIa-c is covalently joined to a ULM, a chemical linker        group (L), a CLM, an ILM, a VLM, MLM, a ULM′, a CLM′, a ILM′, a        VLM′, a MLM′, or combination thereof.

In any aspect or embodiment described herein, the PTM is represented byFormula PTM-XIIa, PTM-XIIb, PTM-XIIc, PTM-XIId, PTM-XIIe, or PTM-XIIf:

wherein:

-   -   B of PTM-XIIa-f is CH, N or S; D of PTM-XII is CH or N; E of        PTM-XII is CH or N; F of PTM-XII is CH or N; G of PTM-XII is CH        or N; and J of PTM-XII is C or N, wherein when B is S then D is        CH, E is N, F is CH, G is N and J is C;    -   X of PTM-XIIa-f is O, S, CH₂ or N;    -   m of PTM-XIIa-f is 0 or 1;    -   n of PTM-XIIa-f is 0, 1, 2, 3 or 4;    -   Ring A of PTM-XIIa-f is aryl, heterocyclyl, pyridinyl,        pyrazolyl, thiophenyl, furanyl or phenyl;    -   R₁ of PTM-XIIa-f is independently selected from (C₁-C₄)alkyl,        (C₃-C₆)cycloalkyl, heterocyclyl, CF₃, CHF₂, CN, halo,        pyrimidine, piperidine and phenyl, each optionally substituted        with (C₁-C₄)alkyl, OH, CH₃, OCH₃, halo, O(C₁-C₄)alkyl,        methyl-piperidine, S(O)₂R^(c), C(O)N(R^(b))₂, or        C(O)O(C₁-C₄)alkyl;    -   R₂ of PTM-XIIa-f is absent or H and R₃ is independently selected        from: (C₁-C₄)alkyl, (C₁-C₆)alkyl, (C₃-C₈)cycloalkyl,        heterocyclyl, pyranyl, cyclopentyl, cyclohexyl, cycloheptyl,        thiopyranyl, pyrazolyl, piperidinyl, morpholinyl, piperazinyl,        each optionally substituted with one or more substituents        independently selected from halo, OH, oxo, N(R_(b))₂,        oxopyrrolidinyl, or morpholinyl, or R₂ and R₃ can be taken        together with the nitrogen to which they are attached to form a        heterocyclyl, piperazine or morpholine, each optionally        substituted with one or more substituents selected from oxo and        R_(a);    -   R₄ of PTM-XIIa-f is independently H or methyl;    -   R_(a) of PTM-XIIa-f is independently selected from (C₁-C₄)alkyl,        (C₃-C₆)cycloalkyl, cyclopropyl, CF₃, F, CHF₂, OH, halo and NH₂,        said alkyl optionally substituted with (C₃-C₆)cycloalkyl and        CF₃; and    -   R_(b) of PTM-XIIa-f is independently selected from H and        (C₁-C₄)alkyl;    -   R^(C) of PTM-XIIa-f is methyl; and    -   the PTM-XIIa-f is covalently joined to a ULM, a chemical linker        group (L), a CLM, an ILM, a VLM, MLM, a ULM′, a CLM′, a ILM′, a        VLM′, a MLM′, or combination thereof.

In any aspect or embodiment described, the PTM is represented by FormulaPTM-XIIIa, PTM-XIIIb, PTM-XIIIc, PTM-XIIId, PTM-XIIIe, PTM-XIIIf,PTM-XIIIg, PTM-XIIIh, PTM-XIIIi, or PTM-XIIIj:

wherein:

-   -   Ring Z₁ of PTM-XIIIa-j is an optionally substituted heteroaryl;    -   Ring Z₂ of PTM-XIIIa-j is a optionally substituted        heterocycloalkyl, optionally substituted heteroaryl or a direct        bond;    -   R₁ of PTM-XIIIa-j is optionally substituted alkyl, optionally        substituted hydroxyalkyl cyano, —NR_(a)R_(b), optionally        substituted cycloalkyl, optionally substituted aryl or        optionally substituted heterocyclyl; wherein the substituent, at        each occurrence, independently is alkyl, alkoxy, halogen,        hydroxyl, hydroxyalkyl, amino, aminoalkyl, nitro, cyano,        haloalkyl, haloalkoxy, —OCO—CH₂—O-alkyl, —OP(O)(O-alkyl)₂ or        —CH₂—OP(O)(O-alkyl)₂;    -   R₂ of PTM-XIIIa-j, at each occurrence, independently is an        optionally substituted group selected from alkyl, cycloalkyl, or        cycloheteroalkyl; wherein the substituent, at each occurrence,        is independently halogen, alkoxy, hydroxyl, hydroxyalkyl,        haloalkyl or haloalkoxy;    -   R_(2a) of PTM-XIIIa-j is an H or optionally substituted alkyl        (e.g., optionally substituted C₁-C₄ alkyl);    -   R₃ of PTM-XIIIa-j, at each occurrence, independently is        hydrogen, halogen, alkyl, haloalkyl, haloalkoxy, alkoxy,        —NR_(a)R_(b), hydroxyl or hydroxyalkyl;    -   R₄ of PTM-XIIIa-j at each occurrence is independently is        halogen, cyano, an unsubstituted or a singly or multiply,        identically or differently substituted C₁-C₅-alkyl or an        unsubstituted or a singly or multiply, identically or        differently substituted C₃-C₆-cycloalkyl (e.g., the substituents        of the alkyl or cycloalkyl may be selected from the group of        halogen and hydroxyl);    -   R₅ of PTM-XIIIa-j at each occurrence is independently is        hydrogen, halogen or an unsubstituted or        poly-halogen-substituted C₁-C₅-alkyl;    -   R₆ of PTM-XIIIa-j at each occurrence is independently optionally        substituted C₁-C₆-alkyl (e.g., C₁-C₆-alkyl radical        unsubstituted, monobustituted or polysubstituted identically or        differently by halogen, hydroxyl, an unsubstituted or mono- or        poly-halogen-substituted C₃-C₆-cycloalkyl, or an R⁹, R¹⁰SO₂,        R¹⁰SO or R¹¹O radical, or a group selected from:

wherein * represents the bonding site of the group to the rest for themolecule);

-   -   R₇ and R₈ of PTM-XIIIa-j at each occurrence is independently        selected from hydrogen or C₁-C₆-alkyl (e.g., both may be H or a        C₁-C₆ alkyl, including the same C₁-C₆ alkyl);    -   R₉ of PTM-XIIIa-j is an unsubstituted or mono- or        di-methyl-substituted monocyclic saturated heterocycle having 4        to 6 ring atoms, which contains a heteroatom or a heterogroup        from the group of O, S, SO and SO₂;    -   R₁₀ of PTM-XIIIa-j is a C1-C6-alkyl, where the C1-C5-alkyl        radical is unsubstituted or mono- or polysubstituted identically        or differently by halogen, hydroxyl or C3-C5-cycloalkyl; or R₁₀        is C3-C6-cycloalkyl    -   R₁₁ of PTM-XIIIa-j is an optionally substituted C1-C6-alkyl        (e.g., a C1-C6-alkyl radical is unsubstituted or mono- or        polysubstituted identically or differently by, e.g., halogen);    -   R_(a) of PTM-XIIIa-j is hydrogen or alkyl;    -   R_(b) of PTM-XIIIa-j is hydrogen, alkyl, acyl, hydroxyalkyl,        —SO₂-alkyl or optionally substituted cycloalkyl;    -   R₁₂ of PTM-XIIIa-j is optionally substituted C1-C5 alkyl,        optionally substituted methyl, optionally substituted ethyl,        optionally substituted cyloalky, or

-   -   R₁₃ of PTM-XIIIa-j is H or methyl;    -   R₁₄ of PTM-XIIIa-j is an optionally substituted linear or        branched alkyl (e.g., optionally substituted linear or branched        C1-C8 alkyl), optionally substituted amide, carboxylic group,        optionally substituted cycloalkyl, optionally substituted        heterocycloalkyl, optionally substituted aryl (e.g., optionally        substituted C5-C7 aryl), optionally substituted heteroaryl        (e.g., optionally substituted C5-C7 heteroaryl), —SO₂-alkyl,        —SO₂H, —O-alkyl, —O-aryl, —O-heteroaryl, optionally substituted        urea group;    -   W and Y of PTM-XIIIa-j are selected from C and N with the        proviso that one is N and one is C;    -   X of PTM-XIIIa-j is CH or N;    -   “m” of PTM-XIIIa-j is 1 or 2;    -   “n” of PTM-XIIIa-j is 1 or 2; and    -   the PTM-XIIIa-j is covalently joined to a ULM, a chemical linker        group (L), a CLM, an ILM, a VLM, MLM, a ULM′, a CLM′, a ILM′, a        VLM′, a MLM′, or combination thereof.

In aspect or embodiment described herein, the ULM is a Von Hippel-Lindau(VHL) ligase-binding moiety (VLM) with a chemical structure representedby:

wherein:

-   -   X¹, X² are each independently selected from the group of a bond,        O, NR^(Y3), CR^(Y3)R^(Y4), C═O, C═S, SO, and SO₂;    -   R^(Y3), R^(Y4) are each independently selected from the group of        H, linear or branched C₁₋₆ alkyl, optionally substituted by 1 or        more halo, optionally substituted C₁₋₆ alkoxyl (e.g., optionally        substituted by 1-3 R^(p) groups);    -   R^(P) is 0, 1, 2, or 3 groups, each independently selected from        the group H, halo, —OH, C₁₋₃ alkyl, C═O;    -   W³ is selected from the group of an optionally substituted T, an        optionally substituted -T-N(R^(1a)R^(1b))X³, optionally        substituted -T-N(R^(1a)R^(1b)), optionally substituted -T-Aryl,        an optionally substituted -T-Heteroaryl, an optionally        substituted T-biheteroaryl, an optionally substituted        -T-Heterocycle, an optionally substituted -T-biheterocycle, an        optionally substituted —NR¹-T-Aryl, an optionally substituted        —NR¹-T-Heteroaryl or an optionally substituted        —NR¹-T-Heterocycle;    -   X³ is C═O, R¹, R^(1a), R^(1b);    -   each of R¹, R^(1a), R^(1b) is independently selected from the        group consisting of H, linear or branched C₁-C₆ alkyl group        optionally substituted by 1 or more halo or —OH groups,        R^(Y3)C═O, R^(Y3)C═S, R^(Y3)SO, R^(Y3)SO₂, N(R^(Y3)R^(Y4))C═O,        N(R^(Y3)R^(Y4))C═S, N(R^(Y3)R^(Y4))SO, and N(R^(Y3)R^(Y4))SO₂;    -   T is selected from the group of an optionally substituted alkyl,        —(CH₂)_(n)— group, wherein each one of the methylene groups is        optionally substituted with one or two substituents selected        from the group of halogen, methyl, optionally substituted        alkoxy, a linear or branched C₁-C₆ alkyl group optionally        substituted by 1 or more halogen, C(O) NR¹R^(1a), or NR₁R^(1a)        or R¹ and R^(1a) are joined to form an optionally substituted        heterocycle, or —OH groups or an amino acid side chain        optionally substituted; and    -   n is 0 to 6,    -   W⁴ is

-   -   R_(14a), R_(14b), are each independently selected from the group        of H, haloalkyl, or optionally substituted alkyl;    -   W⁵ is selected from the group of a phenyl or a 5-10 membered        heteroaryl,    -   R₁₅ is selected from the group of H, halogen, CN, OH, NO₂, N        R_(14a)R_(14b), OR_(14a), CONR_(14a)R_(14b), NR_(14a)COR_(14b),        SO₂NR_(14a)R_(14b), NR_(14a) SO₂R_(14b), optionally substituted        alkyl, optionally substituted haloalkyl, optionally substituted        haloalkoxy, optionally substituted aryl, optionally substituted        heteroaryl, optionally substituted cycloalkyl, or optionally        substituted cycloheteroalkyl;    -   and wherein the dashed line indicates the site of attachment of        at least one PTM, another ULM (ULM′) or a chemical linker moiety        coupling at least one PTM or a ULM′ or both to ULM.

In aspect or embodiment described herein, the ULM is a Von Hippel-Lindau(VHL) ligase-binding moiety (VLM) with a chemical structure representedby:

wherein:

-   -   W³ is selected from the group of an optionally substituted aryl,        optionally substituted heteroaryl, or

-   -   R₉ and R₁₀ are independently hydrogen, optionally substituted        alkyl, optionally substituted cycloalkyl, optionally substituted        hydroxyalkyl, optionally substituted heteroaryl, or haloalkyl,        or R₉, R₁₀, and the carbon atom to which they are attached form        an optionally substituted cycloalkyl;    -   R₁₁ is selected from the group of an optionally substituted        heterocyclic, optionally substituted alkoxy, optionally        substituted heteroaryl, optionally substituted aryl,

-   -   R₁₂ is selected from the group of H or optionally substituted        alkyl;    -   R₁₃ is selected from the group of H, optionally substituted        alkyl, optionally substituted alkylcarbonyl, optionally        substituted (cycloalkyl)alkylcarbonyl, optionally substituted        aralkylcarbonyl, optionally substituted arylcarbonyl, optionally        substituted (heterocyclyl)carbonyl, or optionally substituted        aralkyl;    -   R_(14a), R_(14b), are each independently selected from the group        of H, haloalkyl, or optionally substituted alkyl;    -   W⁵ is selected from the group of a phenyl or a 5-10 membered        heteroaryl,    -   R₁₅ is selected from the group consisting of H, halogen, CN, OH,        NO₂, N R_(14a)R_(14b), OR^(14a), CONR_(14a)R_(14b),        NR_(14a)COR_(14b), SO₂NR_(14a)R_(14b), NR_(14a) SO₂R_(14b),        optionally substituted alkyl, optionally substituted haloalkyl,        optionally substituted haloalkoxy, optionally substituted aryl,        optionally substituted heteroaryl, optionally substituted        cycloalkyl, or optionally substituted cycloheteroalkyl;    -   R₁₆ is independently selected from the group consisting of halo,        optionally substituted alkyl, optionally substituted haloalkyl,        hydroxy, or optionally substituted haloalkoxy;    -   o is 0, 1, 2, 3, or 4;    -   R₁₈ is independently selected from the group consisting of H,        halo, optionally substituted alkoxy, cyano, optionally        substituted alkyl, haloalkyl, haloalkoxy or a linker; and    -   p is 0, 1, 2, 3, or 4, and wherein the dashed line indicates the        site of attachment of at least one PTM, another ULM (ULM′) or a        chemical linker moiety coupling at least one PTM or a ULM′ or        both to ULM.

In aspect or embodiment described herein, the ULM has a chemicalstructure selected from the group of:

wherein:

-   -   R₁ is H, ethyl, isopropyl, tert-butyl, sec-butyl, cyclopropyl,        cyclobutyl, cyclopentyl, or cyclohexyl; optionally substituted        alkyl, optionally substituted hydroxyalkyl, optionally        substituted heteroaryl, or haloalkyl;    -   R_(14a) is H, haloalkyl, optionally substituted alkyl, methyl,        fluoromethyl, hydroxymethyl, ethyl, isopropyl, or cyclopropyl;    -   R₁₅ is selected from the group consisting of H, halogen, CN, OH,        NO₂, optionally substituted heteroaryl, optionally substituted        aryl; optionally substituted alkyl, optionally substituted        haloalkyl, optionally substituted haloalkoxy, optionally        substituted cycloalkyl, or optionally substituted        cycloheteroalkyl;    -   X is C, CH₂, or C═O    -   R₃ is absent or an optionally substituted 5 or 6 membered        heteroaryl; and    -   wherein the dashed line indicates the site of attachment of at        least one PTM, another ULM (ULM′) or a chemical linker moiety        coupling at least one PTM or a ULM′ or both to the ULM.

In aspect or embodiment described herein, the ULM comprises a groupaccording to the chemical structure:

wherein:

-   -   R_(14a) is H, haloalkyl, optionally substituted alkyl, methyl,        fluoromethyl, hydroxymethyl, ethyl, isopropyl, or cyclopropyl;    -   R9 is H;    -   R10 is H, ethyl, isopropyl, tert-butyl, sec-butyl, cyclopropyl,        cyclobutyl, cyclopentyl, or cyclohexyl;

R11 is

optionally substituted heteroaryl,

-   -   p is 0, 1, 2, 3, or 4; and    -   each R₁₈ is independently halo, optionally substituted alkoxy,        cyano, optionally substituted alkyl, haloalkyl, haloalkoxy or a        linker;    -   R12 is H, C═O    -   R13 is H, optionally substituted alkyl, optionally substituted        alkylcarbonyl, optionally substituted (cycloalkyl)alkylcarbonyl,        optionally substituted aralkylcarbonyl, optionally substituted        arylcarbonyl, optionally substituted (heterocyclyl)carbonyl, or        optionally substituted aralkyl,    -   R₁₅ is selected from the group consisting of H, halogen, Cl, CN,        OH, NO₂, optionally substituted heteroaryl, optionally        substituted aryl;

-   -   and wherein the dashed line indicates the site of attachment of        at least one PTM, another ULM (ULM′) or a chemical linker moiety        coupling at least one PTM or a ULM′ or both to the ULM.

In aspect or embodiment described herein, the ULM is a cereblon E3ligase-binding moiety (CLM) selected from the group consisting of athalidomide, lenalidomide, pomalidomide, analogs thereof, isosteresthereof, or derivatives thereof.

In aspect or embodiment described herein, the CLM has a chemicalstructure represented by:

wherein:

-   -   W is selected from the group consisting of CH₂, CHR, C═O, SO₂,        NH, and N-alkyl;    -   each X is independently selected from the group consisting of O,        S, and H₂;    -   Y is selected from the group consisting of CH₂, —C═CR′, NH,        N-alkyl, N-aryl, N-hetaryl, N-cycloalkyl, N-heterocyclyl, O, and        S;    -   Z is selected from the group consisting of O, S, and H₂;    -   G and G′ are independently selected from the group consisting of        H, optionally substituted linear or branched alkyl, OH, R′OCOOR,        R′OCONRR″, CH₂-heterocyclyl optionally substituted with R′, and        benzyl optionally substituted with R′;    -   Q₁, Q₂, Q₃, and Q₄ represent a carbon C substituted with a group        independently selected from R′, N or N-oxide;    -   A is independently selected from the group H, optionally        substituted linear or branched alkyl, cycloalkyl, C₁ and F;    -   R comprises —CONR′R″, —OR′, —NR′R″, —SR′, —SO₂R′, —SO₂NR′R″,        —CR′R″—, —CR′NR′R″—, (—CR′O)_(n′)R″, -aryl, -hetaryl, optionally        substituted linear or branched -alkyl, -cycloalkyl,        -heterocyclyl, —P(O)(OR′)R″, —P(O)R′R″, —OP(O)(OR′)R″,        —OP(O)R′R″, —Cl, —F, —Br, —I, —CF₃, —CN, —NR′SO₂NR′R″,        —NR′CONR′R″, —CONR′COR″, —NR′C(═N—CN)NR′R″, —C(═N—CN)NR′R″,        —NR′C(═N—CN)R″, —NR′C(═C—NO₂)NR′R″, —SO₂NR′COR″, —NO₂, —CO₂R′,        —C(C═N—OR′)R″, —CR′═CR′R″, —CCR′, —S(C═O)(C═N—R′)R″, —SF₅ and        —OCF₃;    -   R′ and R″ are independently selected from the group consisting        of a bond, H, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclic,        —C(═O)R, heterocyclyl, each of which is optionally substituted;    -   represents a bond that may be stereospecific ((R) or (S)) or        non-stereospecific; and    -   R_(n) comprises from 1 to 4 independently selected functional        groups or atoms, for example, O, OH, N, C1-C6 alkyl, C1-C6        alkoxy, -alkyl-aryl (e.g., an -alkyl-aryl comprising at least        one of C1-C6 alkyl, C4-C7 aryl, or a combination thereof), aryl        (e.g., C5-C7 aryl), amine, amide, or carboxy,    -   n′ is an integer from 1-10 (e.g., 1-4, 1, 2, 3, 4, 5, 6, 7, 8,        9, or 10), and wherein    -   when n is 1, R_(n) is modified to be covalently joined to the        linker group (L), and    -   when n is 2, 3, or 4, then one R_(n) is modified to be        covalently joined to the linker group (L), and any other R_(n)        is optionally modified to be covalently joined to a PTM, a CLM,        a second CLM having the same chemical structure as the CLM, a        CLM′, a second linker, or any multiple or combination thereof.

In aspect or embodiment described herein, the CLM has a chemicalstructure represented by:

wherein:

-   -   W is independently selected from the group CH2, C═O, NH, and        N-alkyl;    -   R is independently selected from a H, methyl, or optionally        substituted linear or branched alkyl (e.g., optionally        substituted linear or branched C1-C6 alkyl);    -   represents a bond that may be stereospecific ((R) or (S)) or        non-stereospecific; and    -   Rn comprises from 1 to 4 independently selected functional        groups or atoms, for example, O, OH, N, C1-C6 alkyl, C1-C6        alkoxy, -alkyl-aryl (e.g., an -alkyl-aryl comprising at least        one of C1-C6 alkyl, C4-C7 aryl, or a combination thereof), aryl        (e.g., C5-C7 aryl), amine, amide, or carboxy, and optionally,        one of which is modified to be covalently joined to a PTM, a        chemical linker group (L), a CLM (or CLM′) or combination        thereof.

In aspect or embodiment described herein, the ULM is a (MDM2) bindingmoiety (MLM) with a chemical moiety selected from the group consistingof a substituted imidazolines, a substituted spiro-indolinones, asubstituted pyrrolidines, a substituted piperidinones, a substitutedmorpholinones, a substituted pyrrolopyrimidines, a substitutedimidazolopyridines, a substituted thiazoloimidazoline, a substitutedpyrrolopyrrolidinones, and a substituted isoquinolinones.

In aspect or embodiment described herein, the ULM is a IAP E3 ubiquitinligase binding moiety (ILM) comprising the amino acids alanine (A),valine (V), proline (P), and isoleucine (I) or their unnatural mimetics.

In aspect or embodiment described herein, the ULM is a IAP E3 ubiquitinligase binding moiety (ILM) comprising a AVPI tetrapeptide fragment orderivative thereof.

In aspect or embodiment described herein, the linker (L) comprises achemical structural unit represented by the formula:

-(A^(L))_(q)-,

wherein:

-   -   (A^(L))_(q) is a group which is connected to at least one of a        ULM moiety, a PTM moiety, or a combination thereof;    -   q is an integer greater than or equal to 1; and    -   each A is independently selected from the group consisting of, a        bond, CR^(L1)R^(L2), O, S, SO, SO₂, NR^(L3), SO₂NR^(L3),        SONR^(L3), CONR^(L3), NR^(L3)CONR^(L4), NR^(L3)SO₂NR₄, CO,        CR^(L1)═CR^(L2), C≡C, SiR^(L1)R^(L2), P(O)R^(L1), P(O)OR^(L1),        NR^(L3)C(═NCN)NR^(L4), NR^(L3)C(═NCN), NR^(L3)C(═CNO₂)NR^(L4),        C₃₋₁₁cycloalkyl optionally substituted with 0-6 R^(L1) and/or        R^(L2) groups, C₃₋₁₁heteocyclyl optionally substituted with 0-6        R^(L1) and/or R^(L2) groups, aryl optionally substituted with        0-6 R^(L1) and/or R^(L2) groups, heteroaryl optionally        substituted with 0-6 R^(L1) and/or R^(L2) groups, where R^(L1)        or R^(L2), each independently are optionally linked to other        groups to form cycloalkyl and/or heterocyclyl moiety, optionally        substituted with 0-4 R^(L5) groups;    -   R^(L1), R^(L2), R^(L3), R^(L4) and R^(L5) are, each        independently, H, halo, C₁₋₈alkyl, OC₁₋₈alkyl, SC₁₋₈alkyl,        NHC₁₋₈alkyl, N(C₁₋₈alkyl)₂, C₃₋₁₁cycloalkyl, aryl, heteroaryl,        C₃₋₁₁heterocyclyl, OC₁₋₈cycloalkyl, SC₁₋₈cycloalkyl,        NHC₁₋₈cycloalkyl, N(C₁₋₈cycloalkyl)₂,        N(C₁₋₈cycloalkyl)(C₁₋₈alkyl), OH, NH₂, SH, SO₂C₁₋₈alkyl,        P(O)(OC₁₋₈alkyl)(C₁₋₈alkyl), P(O)(OC₁₋₈alkyl)₂, CC—C₁₋₈alkyl,        CCH, CH═CH(C₁₋₈alkyl), C(C₁₋₈alkyl)═CH(C₁₋₈alkyl),        C(C₁₋₈alkyl)═C(C₁₋₈alkyl)₂, Si(OH)₃, Si(C₁₋₈alkyl)₃,        Si(OH)(C₁₋₈alkyl)₂, COC₁₋₈alkyl, CO₂H, halogen, CN, CF₃, CHF₂,        CH₂F, NO₂, SF₅, SO₂NHC₁₋₈alkyl, SO₂N(C₁₋₈alkyl)₂, SONHC₁₋₈alkyl,        SON(C₁₋₈alkyl)₂, CONHC₁₋₈alkyl, CON(C₁₋₈alkyl)₂,        N(C₁₋₈alkyl)CONH(C₁₋₈alkyl), N(C₁₋₈alkyl)CON(C₁₋₈alkyl)₂,        NHCONH(C₁₋₈alkyl), NHCON(C₁₋₈alkyl)₂, NHCONH₂,        N(C₁₋₈alkyl)SO₂NH(C₁₋₈alkyl), N(C₁₋₈alkyl) SO₂N(C₁₋₈alkyl)₂, NH        SO₂NH(C₁₋₈alkyl), NH SO₂N(C₁₋₈alkyl)₂, NH SO₂NH₂.

In aspect or embodiment described herein, the linker (L) comprises agroup represented by a general structure selected from the groupconsisting of:

—N(R)—(CH₂)_(m)—O(CH₂)_(n)—O(CH₂)_(o)—O(CH₂)_(p)—O(CH₂)_(q)—O(CH₂)_(r)-OCH₂—,—O—(CH₂)_(m)—O(CH₂)_(n)—O(CH₂)_(o)—O(CH₂)_(p)—O(CH₂)_(q)—O(CH₂)_(r)-OCH₂—,—O—(CH₂)_(m)—O(CH₂)_(n)—O(CH₂)_(o)—O(CH₂)_(p)—O(CH₂)_(q)—O(CH₂)_(r)—O—;—N(R)—(CH₂)_(m)—O(CH₂)_(n)—O(CH₂)_(o)—O(CH₂)_(p)—O(CH₂)_(q)—O(CH₂)_(r)—O—;—(CH₂)_(m)—O(CH₂)_(n)—O(CH₂)_(o)—O(CH₂)_(p)—O(CH₂)_(q)—O(CH₂)_(r)—O—;(CH₂)_(m) O(CH₂)_(n)O(CH₂)_(o)—O(CH₂)_(p)—O(CH₂)_(q)—O(CH₂)_(r)-OCH₂—;

wherein each m, n, o, p, q, and r is independently 0, 1, 2, 3, 4, 5, 6with the proviso that when the number is zero, there is no N—O or O—Obond, R is selected from the group H, methyl and ethyl, and X isselected from the group H and F;

In aspect or embodiment described herein, the linker (L) is selectedfrom the group consisting of:

In aspect or embodiment described herein, the linker (L) is selectedfrom the group consisting of:

wherein each m, n, o, p, q, r, and s is independently 0, 1, 2, 3, 4, 5,6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.

In any aspect or embodiment described herein, the linker (L) is selectedfrom:

In any aspect or embodiment described herein, the linker (L) comprisesthe following chemical structure:

wherein:

-   -   W^(L1) and W^(L2) are each independently a 4-8 membered ring        with 0-4 heteroatoms, optionally substituted with RQ, each RQ is        independently a H, halo, OH, CN, CF3, C1-C6 alkyl (linear,        branched, optionally substituted), C1-C6 alkoxy (linear,        branched, optionally substituted), or 2 RQ groups taken together        with the atom they are attached to, form a 4-8 membered ring        system containing 0-4 heteroatoms;    -   Y^(L1) is each independently a bond, C1-C6 alkyl (linear,        branched, optionally substituted) and optionally one or more C        atoms are replaced with O; or C1-C6 alkoxy (linear, branched,        optionally substituted);    -   n is 0-10; and        a dashed line indicates the attachment point to the PTM or ULM        moieties.

In any aspect or embodiment described herein, the linker (L) comprisesthe following chemical structure:

wherein:

-   -   W^(L1) and W^(L2) are each independently aryl, heteroaryl,        cyclic, heterocyclic, C₁₋₆ alkyl, bicyclic, biaryl,        biheteroaryl, or biheterocyclic, each optionally substituted        with R^(Q), each R^(Q) is independently a H, halo, OH, CN, CF₃,        hydroxyl, nitro, C≡CH, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁-C₆ alkyl        (linear, branched, optionally substituted), C₁-C₆ alkoxy        (linear, branched, optionally substituted), OC₁₋₃alkyl        (optionally substituted by 1 or more —F), OH, NH₂,        NR^(Y1)R^(Y2), CN, or 2 R^(Q) groups taken together with the        atom they are attached to, form a 4-8 membered ring system        containing 0-4 heteroatoms;    -   Y^(L1) is each independently a bond, NR^(YL1), O, S, NR^(YL2),        CR^(YL1)R^(YL2), C═O, C═S, SO, SO₂, C₁-C₆ alkyl (linear,        branched, optionally substituted) and optionally one or more C        atoms are replaced with O; C₁-C₆ alkoxy (linear, branched,        optionally substituted);    -   Q^(L) is a 3-6 membered alicyclic or aromatic ring with 0-4        heteroatoms, optionally bridged, optionally substituted with 0-6        R^(Q), each R^(Q) is independently H, C₁₋₆ alkyl (linear,        branched, optionally substituted by 1 or more halo, C₁₋₆        alkoxyl), or 2 R^(Q) groups taken together with the atom they        are attached to, form a 3-8 membered ring system containing 0-2        heteroatoms);    -   R^(YL1), R^(YL2) are each independently H, OH, C₁₋₆ alkyl        (linear, branched, optionally substituted by 1 or more halo,        C₁₋₆ alkoxyl), or R¹, R² together with the atom they are        attached to, form a 3-8 membered ring system containing 0-2        heteroatoms);    -   n is 0-10; and    -   a dashed line indicates the attachment point to the PTM or ULM        moieties.

In any aspect or embodiment described herein, the linker (L) is selectedfrom the group consisting of:

In any aspect or embodiment described herein, the linker (L) is apolyethylenoxy group optionally substituted with aryl or phenylcomprising from 1 to 10 ethylene glycol units.

In any aspect or embodiment described herein, the PTM is selected fromthe group consisting of:

In any aspect or embodiment described herein, the compound comprisesmultiple ULMs, multiple PTMs, multiple linkers or any combinationsthereof.

In another aspect, the present disclosure provides for a composition.The composition comprises an effective amount of a bifunctional compoundof present disclosure, and a pharmaceutically acceptable carrier.

In aspect or embodiment described herein, the composition furthercomprises at least one of additional bioactive agent or anotherbifunctional compound of the present disclosure.

In aspect or embodiment described herein, the additional bioactive agentis anti-neurodegenerative agent, an anti-inflammatory agent, and/or ananti-cancer agent.

A composition comprising a pharmaceutically acceptable carrier and aneffective amount of at least one compound of the present disclosure fortreating a disease or disorder in a subject, the method comprisingadministering the composition to a subject in need thereof, wherein thecompound is effective in treating or ameliorating at least one symptomof the disease or disorder.

In any aspect or embodiment described herein, the disease or disorder isassociated with tau accumulation and aggregation.

In any aspect or embodiment described herein, the disease or disorder isa neurodegenerative disease or disorder, an inflammatory disease ordisorder and/or a cancer associated with IRAK-4 accumulation andaggregation.

In any aspect or embodiment described herein, the cancer issquamous-cell carcinoma, basal cell carcinoma, adenocarcinoma,hepatocellular carcinomas, and renal cell carcinomas, cancer of thebladder, bowel, breast, cervix, colon, esophagus, head, kidney, liver,lung, neck, ovary, pancreas, prostate, and stomach; leukemias; benignand malignant lymphomas, particularly Burkitt's lymphoma andNon-Hodgkin's lymphoma; benign and malignant melanomas;myeloproliferative diseases; sarcomas, including Ewing's sarcoma,hemangiosarcoma, Kaposi's sarcoma, liposarcoma, myosarcomas, peripheralneuroepithelioma, synovial sarcoma, gliomas, astrocytomas,oligodendrogliomas, ependymomas, gliobastomas, neuroblastomas,ganglioneuromas, gangliogliomas, medulloblastomas, pineal cell tumors,meningiomas, meningeal sarcomas, neurofibromas, and Schwannomas; bowelcancer, breast cancer, prostate cancer, cervical cancer, uterine cancer,lung cancer, ovarian cancer, testicular cancer, thyroid cancer,astrocytoma, esophageal cancer, pancreatic cancer, stomach cancer, livercancer, colon cancer, melanoma; carcinosarcoma, Hodgkin's disease,Wilms' tumor and teratocarcinomas. Additional cancers which may betreated using compounds according to the present disclosure include, forexample, T-lineage Acute lymphoblastic Leukemia (T-ALL), T-lineagelymphoblastic Lymphoma (T-LL), Peripheral T-cell lymphoma, Adult T-cellLeukemia, Pre-B ALL, Pre-B Lymphomas, Large B-cell Lymphoma, BurkittsLymphoma, B-cell ALL, Philadelphia chromosome positive ALL andPhiladelphia chromosome positive CML.

In any aspect or embodiment described herein, the inflammatory diseaseor disorder is selected from the group consisting of ocular allergy,conjunctivitis, keratoconjunctivitis sicca, vernal conjunctivitis,allergic rhinitis, autoimmune hematological disorders (e.g. hemolyticanemia, aplastic anemia, pure red cell anemia and idiopathicthrombocytopenia), systemic lupus erythematosus, rheumatoid arthritis,polychondritis, scleroderma, Wegener granulamatosis, dermatomyositis,chronic active hepatitis, myasthenia gravis, Steven-Johnson syndrome,idiopathic sprue, autoimmune inflammatory bowel disease (e.g. ulcerativecolitis and Crohn's disease), irritable bowel syndrome, celiac disease,periodontitis, hyaline membrane disease, kidney disease, glomerulardisease, alcoholic liver disease, multiple sclerosis, endocrineopthalmopathy, Grave's disease, sarcoidosis, alveolitis, chronichypersensitivity pneumonitis, primary biliary cirrhosis, uveitis(anterior and posterior), Sjogren's syndrome, interstitial lungfibrosis, psoriatic arthritis, systemic juvenile idiopathic arthritis,nephritis, vasculitis, diverticulitis, interstitial cystitis,glomerulonephritis (e.g. including idiopathic nephrotic syndrome orminimal change nephropathy), chronic granulomatous disease,endometriosis, leptospirosis renal disease, glaucoma, retinal disease,headache, pain, complex regional pain syndrome, cardiac hypertrophy,muscle wasting, catabolic disorders, obesity, fetal growth retardation,hypercholesterolemia, heart disease, chronic heart failure,mesothelioma, anhidrotic ecodermal dysplasia, Behcet's disease,incontinentia pigmenti, Paget's disease, pancreatitis, hereditaryperiodic fever syndrome, asthma, acute lung injury, acute respiratorydistress syndrome, eosinophilia, hypersensitivities, anaphylaxis,fibrositis, gastritis, gastroenteritis, nasal sinusitis, ocular allergy,silica induced diseases, chronic obstructive pulmonary disease (COPD),cystic fibrosis, acid-induced lung injury, pulmonary hypertension,polyneuropathy, cataracts, muscle inflammation in conjunction withsystemic sclerosis, inclusion body myositis, myasthenia gravis,thyroiditis, Addison's disease, lichen planus, appendicitis, atopicdermatitis, asthma, allergy, blepharitis, bronchiolitis, bronchitis,bursitis, cervicitis, cholangitis, cholecystitis, chronic graftrejection, colitis, conjunctivitis, cystitis, dacryoadenitis,dermatitis, juvenile rheumatoid arthritis, dermatomyositis,encephalitis, endocarditis, endometritis, enteritis, enterocolitis,epicondylitis, epididymitis, fasciitis, Henoch-Schonlein purpura,hepatitis, hidradenitis suppurativa, immunoglobulin A nephropathy,interstitial lung disease, laryngitis, mastitis, meningitis, myelitismyocarditis, myositis, nephritis, oophoritis, orchitis, osteitis,otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis,pleuritis, phlebitis, pneumonitis, pneumonia, polymyositis, proctitis,prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis,stomatitis, synovitis, tendonitis, tonsillitis, ulcerative colitis,vasculitis, vulvitis, alopecia areata, erythema multiforma, dermatitisherpetiformis, scleroderma, vitiligo, hypersensitivity angiitis,urticaria, bullous pemphigoid, pemphigus vulgaris, pemphigus foliaceus,paraneoplastic pemphigus, epidermolysis bullosa acquisita, acute andchronic gout, chronic gouty arthritis, psoriasis, psoriatic arthritis,rheumatoid arthritis, Cryopyrin Associated Periodic Syndrome (CAPS) andosteoarthritis.

1. A bifunctional compound having the chemical structure:ULM-L-PTM, or a pharmaceutically acceptable salt, enantiomer,stereoisomer, solvate, polymorph or prodrug thereof, wherein: the ULM isa small molecule E3 ubiquitin ligase binding moiety that binds an E3ubiquitin ligase; the PTM is a small molecule comprising anInterleukin-1 Receptor-Associated Kinase 4 (IRAK-4) targeting moiety;and the L is a bond or a chemical linking moiety connecting the ULM andthe PTM.
 2. The bifunctional compound according to claim 1, wherein theE3 ubiquitin ligase binding moiety that targets an E3 ubiquitin ligaseselected from the group consisting of Von Hippel-Lindau (VLM), cereblon(CLM), mouse double-minute homolog2 (MLM), and IAP (ILM).
 3. Thecompound according to claim 1, wherein PTM is represented by FormulaPTM-I:

wherein: X of PTM-I is —N═ or —CH═; Y of PTM-I is selected from thegroup consisting of —NR²—, —CH₂— and —O—; or when Y is —NR²—, R² and R³together with the nitrogen to which they are attached optionally form a4- to 6-membered heterocyclic ring, wherein the 4- to 6-memberedheterocyclic ring is optionally substituted with 1 to 3 substituentsindependently selected from R⁷ groups; R¹ of PTM-I is selected from thegroup consisting of: hydrogen, C₁₋₁₀ alkyl, C₃₋₈ cycloalkyl, aryl,heterocyclyl, halogen, —COOR⁷, —NR⁷, —SR⁷, —OR⁷, —SO₂R⁷, —COR⁷, —NCOR⁷,and —CONR⁷; R² of PTM-I is selected from the group consisting of:hydrogen, C₁₋₁₀ alkyl, and C₃₋₄ cycloalkyl; R³ of PTM-I is selected fromthe group consisting of: hydrogen, C₁₋₁₀ alkyl, C₃₋₄ cycloalkyl, aryl,heterocyclyl, and —COOR⁷; R⁶ of PTM-I is selected from the groupconsisting of: C₁₋₁₀ alkyl, C₃₋₄ cycloalkyl, aryl, heterocyclyl, —COOR⁷,—SO₂R⁷, —COR⁷; and R⁷ of PTM-I is selected from the group consisting of:hydrogen, C₁₋₁₀ alkyl, C₃₋₄ cycloalkyl, aryl, and heteroaryl; whereineach of the C₁₋₁₀ alkyl, C₃₋₄ cycloalkyl, aryl and heterocyclyl of R¹,R³, R⁶ and R⁷ is optionally substituted with 1-4 substituentsindependently selected from the group consisting of C₁₋₄ alkyl, C₁₋₄alkoxy, halogen, —SO₂R⁸ and —OR⁸; and R⁸ of PTM-I is selected from thegroup consisting of hydrogen, and C₁₋₆ alkyl.
 4. The compound of claim1, wherein the PTM is represented by Formula PTM-II:

wherein: R¹ of PTM-II is aryl, heteroaryl, heterocyclyl or (C₁₋₆alkyl)R⁶, wherein said aryl, heteroaryl, and heterocyclyl groups areoptionally substituted with one or two substituents selected from thegroup consisting of halo, cyano, R⁴, C₁₋₃ aminoalkyl, C₁₋₃ hydroxyalkyl,C₃₋₄ cycloalkyl, OR⁴, NR⁴R⁵, NR⁴COR⁶, NR⁴SO₂R⁶, SO₂NR⁴R⁵, CONR⁴R⁵; R² ofPTM-II of PTM-II is aryl, heteroaryl, C₃₋₈ cycloalkyl, heterocyclyl or(C₁₋₆ alkyl)R⁶, wherein said aryl, heteroaryl, cycloalkyl andheterocyclyl groups are optionally substituted with one or twosubstituents selected from the group consisting of halo, cyano, oxo,hydroxyl, imino, hydroxyimino, R⁴, OR⁴, O(C₃₋₈ cycloalkyl), (C═O)OR⁴,SO_(m)R⁶, SO_(m)R⁴, NR⁴R⁵, SO₂NR⁴R⁵ and NR⁴SO₂R⁶; R³ of PTM-II is ahalo, cyano, oxo, hydroxyl, imino, hydroxyimino, R⁴, OR⁴, C₃₋₈cycloalkyl, SO_(m)R⁶, SO_(m)R⁴NR⁴R⁵, or (C═O)NR⁴R⁵, NR⁴(CO)R⁶,SO_(m)NR⁴R⁵ and NR⁴SO₂R⁶; R⁴ of PTM-II is independently hydrogen or C₁₋₆alkyl, wherein said alkyl is optionally substituted with one to threehalo or hydroxyl; R⁵ of PTM-II is independently hydrogen or C₁₋₆ alkyl,wherein said alkyl is optionally substituted with halo or hydroxyl; R⁶of PTM-II is independently aryl, heteroaryl, C₃₋₈ cycloalkyl orheterocyclyl; and m of PTM-II is an integer from zero to two.
 5. Thecompound of claim 1, wherein the PTM is represented by Formula PTM-III:

wherein: R¹ of PTM-III is an optionally substituted aromaticheterocyclic group or an optionally substituted C₆₋₁₄ aryl group; R² ofPTM-III is a hydrogen atom or a substituent; R³ and R⁴ of PTM-III areindependently a hydrogen atom or a substituent, or R³ and R⁴ incombination optionally form an optionally substituted ring; R⁵ and R⁶ ofPTM-III are independently a hydrogen atom or a substituent, or R⁵ and R⁶in combination optionally form an optionally substituted ring; X ofPTM-III is CR⁷R⁸, NR⁹, O or S; R⁷ and R⁸ of PTM-III are independently ahydrogen atom or a substituent, or R⁷ and R⁸ in combination optionallyform an optionally substituted ring; and R⁹ of PTM-III is a hydrogenatom or a substituent.
 6. The compound of claim 1, wherein the PTM isrepresented by Formula PTM-IV:

wherein: HET of PTM-IV is a heteroaryl selected from pyrazolyl, indolyl,pyrrolo[2,3-b]pyridinyl, pyrrolo[2,3-d]pyrimidinyl,pyrazolo[3,4-b]pyridinyl, pyrazolo[3,4-d]pyrimidinyl,2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, imidazo[4,5-b]pyridinyl, andpurinyl, wherein said heteroaryl is substituted with R_(a) and R_(b);R_(a) of PTM-IV is H, F, Cl, Br, —CN, —OH, C₁₋₄ alkyl, C₁₋₄ fluoroalkyl,C₁₋₄ hydroxyalkyl, C₁₋₄ alkoxy, —NH₂, —NH(C₁₋₄ alkyl), —N(C₁₋₄ alkyl)₂,—NH(C₁₋₄ hydroxyalkyl), —NH(C₁₋₄ fluoroalkyl), —NH(C₁₋₆hydroxy-fluoroalkyl), —C(O)NH₂, —CH₂NHC(O)(C₁₋₆ alkyl), —CH₂NHC(O)(C₁₋₆hydroxyalkyl), —CH₂NHC(O)NH(C₁₋₆ alkyl), CH₂NHC(O)NHCH₂(phenyl),—CH₂NHC(O)N(C₁₋₄ alkyl)₂, —CH₂NHC(O)O(C₁₋₄ alkyl), —CH₂NHC(O)(C₃₋₆cycloalkyl), —CH₂NHC(O)(tetrahydrofuranyl), CH₂NHC(O)CH₂(C₃₋₆cycloalkyl), —CH₂NHC(O)CH₂(tetrahydropyranyl), CH₂NHC(O)CH₂(phenyl),—NHC(O)(C₁₋₄ alkyl), pyrrolidinyl, hydroxypyrrolidinyl, or pyridazinyl;R_(b) of PTM-IV is H or —NH₂; R₁ of PTM-IV is: (i) C₁₋₆ alkyl, C₁₋₆fluoroalkyl, C₁₋₆ hydroxyalkyl, C₁₋₈ hydroxy-fluoroalkyl, —(C₁₋₆alkylenyl)O(C₁₋₄ alkyl), —(C₁₋₆ alkylenyl)O(C₁₋₄ fluoroalkyl), —(C₁₋₆fluoroalkylenyl)O(C₁₋₄ alkyl), —(C₁₋₆ fluoroalkylenyl)O(C₁₋₄deuteroalkyl), —(C₁₋₆ fluoroalkylenyl)O(C₁₋₄ fluoroalkyl), —(C₁₋₄fluoroalkylenyl)C(C₃₋₆ cycloalkyl)₂(OH), (C₁₋₄ alkylenyl)NHC(O)(C₁₋₄alkylenyl)OC(O)(C₁₋₃ alkyl), —(C₁₋₆ alkylenyl)NHS(O)₂(C₁₋₄ alkyl),—(C₁₋₆ alkylenyl)_(P)(O)(C₁₋₄ alkoxy)₂, —(C₁₋₆ fluoroalkylenyl)NH(C₁₋₄alkyl), —(C₁₋₆ alkylenyl)C(O)NH(C₁₋₄ alkyl), —(C₁₋₆fluoroalkylenyl)C(O)NH(C₁₋₄ alkyl), —(C₁₋₆ fluoroalkylenyl)C(O)NH(C₁₋₄hydroxyalkyl), or —(C₁₋₆ fluoroalkylenyl)OP(O)(OH)₂; (ii) —(C₁₋₃alkylenyl)R_(x), —(C₁₋₃ fluoroalkylenyl)R_(x), —(C₁₋₃alkylenyl)C(O)R_(x), —(C₁₋₃ alkylenyl)C(O)NHR_(x), —(C₁₋₃fluoroalkylenyl)C(O)R_(x), or —CH₂CF=(tetrahydropyranyl), wherein R_(x)is a cyclic group selected from C₃₋₆ cycloalkyl, tetrazolyl,1,1-dioxidotetrahydrothiophenyl, 1,1-dioxidothiomorpholinyl,oxadiazolyl, piperidinyl, piperazinyl, pyrrolidinyl, oxetanyl,tetrahydrofuranyl, tetrahydropyranyl, pyridinyl, imidazolyl,morpholinyl, phenyl, and triazinyl, wherein each cyclic group issubstituted with zero to 3 substituents independently selected from F,—OH, —CH₃, —C(CH₂)₂OH, —OCH₃, —C(O)CH₂CN, —S(O)₂CH₃, —S(O)₂NH₂,—NHC(O)CH₃, —N(S(O)₂CH₃)₂, —CH₂CH₂(acetamidophenyl),—CH₂CH₂(methoxyphenyl), —CH₂CH₂ (sulfamoylphenyl), oxetanyl, benzyl, andmorpholinyl; (iii) C3-6 cycloalkyl or C4-6 cycloalkenyl, eachsubstituted with zero to 3 substituents independently selected from F,—OH, —CN, C1-3 alkyl, C1-3 alkoxy, —S(C1-3 alkyl), —NO2, —S(O)2(C1-3alkyl), C1-4 hydroxyalkyl, —C(C1-3 alkyl)(OH)(C3-6 cycloalkyl),—CH2C(O)NH(C1-3 alkyl), —NHC(O)(C1-3 alkyl), —NHC(O)(C1-4 hydroxyalkyl),—C(O)NH(C1-3 alkyl), C(O)NH(C1-3 deuteroalkyl), —C(O)NH(C3-6cycloalkyl), —NHC(O)O(C1-3 alkyl), NHS(O)2(C1-3 alkyl), pyridinyl,imidazolyl, pyrazolyl, methylimidazolyl, methylpyrazolyl, and thiazolyl;(iv) tetrahydropyranyl, piperidinyl, pyrazolyl, phenyl, pyridinyl, orpyrimidinyl, each substituted with zero to 1 substituent selected from—OH, C1-3 alkyl, C1-3 fluoroalkyl, C1-4 hydroxyalkyl, C1-3 alkoxy,—C(O)(C1-4 alkyl), S(O)2(C1-4 alkyl), —S(O)2NH(C1-4 alkyl), —NH(C1-3alkyl), —N(C1-3 alkyl)2, O(C1-3 alkylenyl)N(C1-3 alkyl)2,—CH2(morpholinyl), azetidinyl, oxetanyl, tetrahydropyranyl, morpholinyl,piperazinyl, piperidinyl, methylpiperazinyl, methoxypiperidinyl,pyridinyl, pyrimidinyl, methylsulfonyl azetidinyl, andC(O)(methylsulfonyl azetidinyl); or (v) pyrrolo[2,3-c]pyridinyl,bicyclo[2.2.1]heptan-1-ol, tetrahydrobenzo[d]thiazol-2-amine, or1,3-diazaspiro[4.5]decane-2,4-dione; and R₂ is: (i) C₁₋₇ alkyl or C₂₋₆alkenyl, each substituted with zero to three substituents independentlyselected from F, —OH, and —CN; —(C₁₋₄ alkylenyl)O(C₁₋₄ alkyl), —(C₁₋₄alkylenyl)O(C₁₋₄ fluoroalkyl), —(C₁₋₆ alkylenyl)NH2, —(C₁₋₆alkylenyl)S(O)₂(C₁₋₃ alkyl), —(C₁₋₆ fluoroalkylenyl)NH(C₁₋₃ alkyl), or—(C₁₋₆ alkylenyl)NHC(O)(C₁₋₄ fluoroalkyl); (ii) —(C₁-4 alkylenyl)R_(y)wherein R_(y) is C₃₋₆ cycloalkyl, azetidinyl, oxetanyl, oxazolyl,pyridinyl, tetrahydropyranyl, or morpholinyl, each substituted with zeroto 2 substituents independently selected from F, —OH, and C₁₋₃ alkyl;(iii) C₃₋₆ cycloalkyl, azetidinyl, oxetanyl, furanyl, tetrahydrofuranyl,pyrrolidinyl, piperidinyl, or tetrahydropyranyl, each substituted withzero to 3 substituents independently selected from F, —OH, C₁₋₃ alkyl,C₁-3 hydroxyalkyl, —C(O)(C₁₋₃ alkyl), —C(O)(C₁₋₃ fluoroalkyl),—C(O)(C₁₋₃ cyanoalkyl), C(O)O(C₁₋₃ alkyl), —C(O)NH₂, —C(O)NH(C₁₋₃alkyl), —C(O)(difluorophenyl), —NH₂, —NH(C₁₋₃ alkyl), —NH(C₁₋₃fluoroalkyl), —NH(oxetanyl), —NHC(O)(C₁₋₃ alkyl), NHC(O)(C₁₋₃fluoroalkyl), —NHC(O)(C₃₋₆ cycloalkyl), —NHC(O)(fluorophenyl),S(O)₂(C₁₋₃ alkyl), imidazolyl, phenyl, pyrimidinyl, fluoropyrimidinyl,chloropyrimidinyl, and methoxypyrimidinyl; (iv) adamantanyl,hydroxyadamantanyl, benzo[d]imidazolyl, benzo[d]oxazolyl,benzo[d]triazolyl, benzothiazolyl, bicyclo[1.1.1]pentanyl, orhydroxybicyclo[2.2.1]heptanyl; or (v) phenyl, pyrazolyl, thiazolyl,thiadiazolyl, or indazolyl, each substituted with 0 to 2 substituentsindependently selected from F, Cl, —OH, —CN, C₁₋₄ alkyl, C₁₋₄hydroxyalkyl, C₁₋₄ fluoroalkyl, C₁₋₄ cyanoalkyl, C₁₋₃ alkoxy, C₃₋₆cycloalkyl, —(C₁₋₃ alkylenyl)O(C₁₋₃ alkyl), —(C₁₋₃ alkylenyl)O(C₁₋₃fluoroalkyl), —C(O)NH₂, —C(O)NH(C₁₋₃ alkyl), —NHC(O)(C₁₋₃ alkyl),—NHC(O)S(O)₂(C₁₋₃ alkyl), —S(O)₂NH₂, S(O)₂(C₁₋₃ alkyl), pyrazolyl,methyl pyrazolyl, imidazolyl, triazolyl, methyl tetrazolyl, ethyltetrazolyl, phenyl, pyrimidinyl, fluoropyrimidinyl, andtetrahydropyranyl.
 7. The compound of claim 1, wherein the PTM isrepresented by Formula PTM-Va or PTM-Vb:

wherein: X₁ and X₃ of PTM-Va or PTM-Vb independently are CH or N; X₂ ofPTM-V is CR₂ or N; provided one and not more than one of X₁, X₂ or X₃ isN; Y of PTM-Va or PTM-Vb is —CH₂— or O; Ring Z of PTM-Va or PTM-Vb isaryl, heteroaryl, or heterocyclyl; A of PTM-Va or PTM-Vb is O, S, or NH;R₁ of PTM-Va or PTM-Vb at each occurrence, is independently hydrogen,cyano, halo, hydroxy, —NO2, —NR₅R₆, optionally substituted alkyl,optionally substituted aryl, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substitutedheterocyclyl or optionally substituted heteroaryl, wherein thesubstituent, in each occurrence, is independently selected from alkyl,alkoxy, haloalkyl, cyano, aminoalkyl, halo, hydroxyl, hydroxyalkyl,—NR⁷R⁸, or COOR⁹; R₂ of PTM-Va or PTM-Vb is hydrogen, optionallysubstituted cycloalkyl, optionally substituted aryl, optionallysubstituted heterocyclyl or —NR_(a)R_(b); wherein the substituent isalkyl, amino, halo or hydroxyl; R₃ of PTM-V, at each occurrence, isindependently selected from hydrogen, carboxy, cyano, hydroxy,hydroxyalkyl, alkyl, aryl, heteroaryl, —SO₂R⁷, hydroxyl or oxo; R₄ ofPTM-Va or PTM-Vb at each occurence is independently selected fromhydrogen, halogen, alkyl, aryl, heterocycloalkyi, heterocycloalkylalkyl,heteroaryl, Y-arylalkyl or —Y-cycloalkyl; wherein cycloalkyl, aryl,heterocycloalkyi, heterocycloalkylalkyl, heteroaryl and arylalkyl can beoptionally substituted with hydroxy, alkyl, haloalkyl, cyano or halo; Y₁of PTM-Va or PTM-Vb is selected from direct bond, O, —C(O)— or NR⁹; R₅and R₆ of PTM-Va or PTM-Vb are independently selected from hydrogen,hydroxyalkyl, aminoalkyl, acyl, optionally substituted alkyl, optionallysubstituted heterocyclyl, optionally substituted aryl; wherein theoptional substituent, in each occurrence, is independently selected fromhalo, haloalkyl or —COOR₉; R₇ and R₈ of PTM-Va or PTM-Vb areindependently hydrogen, alkyl, acyl, heterocyclyl, —COR₉ or —COOR₉; R₉of PTM-V or PTM-Vb at each occurence is independently selected fromhydrogen or alkyl; R_(9a) of PTM-Vb is selected from hydrogen, halo,optionally substituted alkoxy (e.g., optionally substituted C1-C4alkoxy), optionally substituted alkyl (e.g., C1-C4 alkyl optionallysubstituted with halo or hydroxy), hydroxyalkyl (e.g. C1-C4hydroxyalkyl), or haloalkyl (e.g., C1-C4 haloalkyl); “m”, “n” and “q” ofPTM-Va or PTM-Vb are independently selected from 0, 1, 2, or 3; and “p”of PTM-Va or PTM-Vb is 0 or
 1. 8. The compound of claim 1, wherein thePTM is represented by Formula PTM-VIa, PTM-VIb, or PTM-VIc:

wherein: X of PTM-VIa-c is CH or N; a of PTM-VIa-c is 0 or 1; b ofPTM-VIa-c is 0 or 1; m of PTM-VIa-c is 0, 1 or 2; Ring A of PTM-VIa-c is(C₃-C₈)cycloalkyl, (C₃-C₈)cycloalkenyl, aryl or heterocycle optionallysubstituted with one to three substituents independently selected fromR₁; R₁ of PTM-VIa-c is selected from: H, oxo,(C═O)_(a)O_(b)(C₁-C₁₀)alkyl, (C═O)_(a)O_(b)-aryl,(C═O)_(a)O_(b)(C₂-C₁₀)alkenyl, (C═O)_(a)O_(b)(C₂-C₁₀)alkynyl, CO₂H,halo, OH, O_(b)(C₁-C₆)fluoroalkyl, (C═O)_(a)NR₅R⁶, CN,(C═O)_(a)O_(b)(C₃-C₈)cycloalkyl, S(O)_(m)NR₅R₆, SH,S(O)_(m)—(C₁-C₁₀)alkyl and (C═O)_(a)O_(b)-heterocyclyl, said alkyl,aryl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl are optionallysubstituted with one or more substituents selected from R_(a); R₂ and R₃of PTM-VIa-c are independently selected from: H, (C═O)_(a)O_(b)C₁-C₁₀alkyl, (C═O)_(a)O_(b)aryl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl,(C═O)_(a)O_(b) heterocyclyl, CO₂H, CN, O_(b)C1-C₆ fluoroalkyl,O_(a)(C═O)_(b)NR₅R₆, CHO, (N═O)R₅R⁶, S(O)_(m)NR₅R₆, SH, S(O)_(m)(C₁-C₁₀)alkyl, (C═O)_(a)O_(b)C₃-C₈ cycloalkyl, optionally substitutedwith one or more substituents selected from R₁; or R₂ and R₃ can betaken together with the nitrogen to which they are attached to form amonocyclic or bicyclic heterocycle with 3-7 members in each ring andoptionally containing, in addition to the nitrogen, one or twoadditional heteroatoms selected from N, O and S, said monocyclic orbicyclic heterocycle optionally substituted with one or moresubstituents selected from R₁; R₄ of PTM-VIa-c is selected from:(C₁-C₆)alkyl and (C₃-C₆)cycloalkyl, optionally substituted with R_(a);R₅ and R₆ of PTM-VIa-c are independently selected from: H, oxo,(C═O)_(a)O_(b)(C₁-C₁₀)alkyl, (C═O)_(a)O_(b)-aryl,(C═O)_(a)O_(b)(C₂-C₁₀)alkenyl, (C═O)_(a)O_(b)(C₂-C₁₀)alkynyl, CO₂H,O_(b)(C₁-C₆)fluoroalkyl, (C═O)_(a)N(R_(a))₂, CN,(C═O)_(a)O_(b)(C₃-C₈)cycloalkyl, S(O)_(m) N(R_(a))₂, SH,S(O)_(m)—(C₁-C₁₀)alkyl and (C═O)_(a)O_(b)-heterocyclyl, said alkyl,aryl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl are optionallysubstituted with one or more substituents selected from R_(a); R_(a) ofPTM-VIa-c is independently selected from R_(b), OH, (C₁-C₆)alkoxy,halogen, cyclopropyl, CO₂H, CN, O_(a)(C═O)_(b)(C₁-C₆)alkyl, oxo, andN(R^(b))₂; and R_(b) of PTM-VIa-c is independently selected from H and(C₁-C₆)alkyl.
 9. The compound of claim 1, wherein the PTM is representedby Formula PTM-VIIa, PTM-VIIb, PTM-VIIc, PTM-VIId, PTM-VIIe, PTM-VIIf,PTM-VIIg, PTM-VIIh, PTM-VIIi, PTM-VIIj, PTM-VIIk, or PTM-VIIm:

wherein: X and X′ of PTM-VIIa-k or PTM-VIIm are each independently CR⁸,N or —N⁺—O—; Y is independently N, —N⁺—O⁻ or CR^(8′); provided that atleast one of X, X′ or Y is neither N nor —N⁺—O⁻ and that no more thanone of X, X′ or Y is —N⁺—O—; R¹ of PTM-VIIa-k or PTM-VIIm is C₁-C₆alkyl;C₂-C₆alkenyl; C₂-C₆alkynyl; —(CR^(3a)R^(3b))_(m)-(3-to 7-memberedcycloalkyl); —(CR^(3a)R^(3b))_(m)-(3- to 7-membered heterocycloalkyl)having one to three heteroatoms; —(CR^(3a)R^(3b))_(m)-(5- to 10-memberedheteroaryl), having one to three heteroatoms; or—(CR^(3a)R^(3b))_(m)—C₆-C₁₂aryl; wherein said alkyl, alkenyl, alkynyl,cycloalkyl, heterocycloalkyl, heteroaryl or aryl is optionallysubstituted with one to five halogen, deuterium, —OR⁵, —SR⁵,—NR^(11a)R^(11b), cyano, C₁-C₆alkyl, C₃-C₆cycloalkyl or —C₁-C₆alkoxy; R²of PTM-VIIa-k or PTM-VIIm is —(CR^(3a)R^(3b))_(m)-(3- to 10-memberedcycloalkyl); (CR^(3a)R^(3b))_(m)-(3- to 10-membered heterocycloalkyl)having one to three heteroatoms; —(CR^(3a)R^(3b))_(m)-(5- to 10 memberedheteroaryl) having one to three heteroatoms; or—(CR^(3a)R^(3b))_(m)—C₆-C₁₂aryl; wherein said cycloalkyl,heterocycloalkyl, heteroaryl or aryl is optionally substituted with oneto five R⁴; and wherein, if the heteroatom on said heterocycloalkyl andheteroaryl is N, said N is optionally substituted with R^(4′); or R² isC₁-C₆alkyl, wherein said alkyl is optionally substituted with NH₂, OH orcyano; R^(3a) and R^(3b) of PTM-VIIa-k or PTM-VIIm for each occurrenceare independently hydrogen or C₁-C₃alkyl; R⁴ of PTM-VIIa-k or PTM-VIImfor each occurrence is independently a bond, deuterium, halogen, cyano,C₁-C₆alkyl, C₂-C₆alkenyl, oxo, —OR⁵, —SR⁵, —S(O)R⁹, —S(O)₂R⁹,NR^(11a)R^(11b), —C(O)R¹⁰, —(CR^(3a)R^(3b))_(n)-(3- to 7-memberedcycloalkyl), —(CR^(3a)R^(3b))_(n)-(4- to 10-membered heterocycloalkyl),having one to three heteroatoms, —(CR^(3a)R^(3b))_(n)-(5- to 10 memberedheteroaryl), having one to three heteroatoms, or—(CR^(3a)R^(3b))_(n)-C₆-C₁₂aryl wherein said alkyl, cycloalkyl,heterocycloalkyl, heteroaryl or aryl is each optionally andindependently substituted with one to five deuterium, halogen, OR⁵,—SR⁵, —NR^(11a)R^(11b) cyano, C₁-C₆alkyl, C₃-C₆cycloalkyl orC₁-C₆alkoxy; or two R⁴ taken together with the respective carbons towhich each are bonded form a 3- to 6-membered cycloalkyl or 4- to6-membered heterocycloalkyl, wherein said cycloalkyl or heterocycloalkylis optionally substituted with one to three halogen, deuterium, —OR⁵,—SR⁵, —NR^(11a)R^(1l)b, cyano or C₁-C₆alkyl or C₁-C₆alkoxy, wherein thealkyl or alkoxy is optionally substituted with halogen, deuterium, —OR⁵,—SR⁵, —NR^(11a)R^(11b) or cyano; and wherein, if a heteroatom on saidheterocycloalkyl is N, said N is optionally substituted with R^(4′);R^(4′) of PTM-VIIa-k or PTM-VIIm is independently C₁-C₆alkyl,C₂-C₆alkenyl, —C(O)R¹⁰, —S(O)₂R⁹, —(CR^(3a)R^(3b))_(n)-(3- to 7-memberedcycloalkyl), —(CR^(3a)R^(3b))_(n)-(4- to 10-membered heterocycloalkyl)or C(O)(CH₂)_(t)CN; wherein said alkyl, alkenyl, cycloalkyl, orheterocycloalkyl is each optionally and independently substituted withone to five deuterium, halogen, OH, cyano or C₁-C₆alkoxy; or R⁴ andR^(4′) taken together with the respective atoms to which each are bondedform a 3- to 6-membered cycloalkyl or 4- to 6-membered heterocycloalkyl,wherein said cycloalkyl or heterocycloalkyl is optionally substitutedwith one to three halogen, deuterium, —OR⁵, —SR⁵, cyano, C₁-C₆alkyl orC₁-C₆alkoxy, wherein the alkyl or alkoxy is optionally substituted withhalogen, deuterium, —OR⁵, —SR⁵, —NR^(11a)R^(11b), or cyano; R^(4a) andR^(4b) of PTM-VIIa-k or PTM-VIIm are each independently hydrogen,deuterium, fluoro, OH, —OR⁵, methyl, ethyl, vinyl, cyclopropyl orpropyl, optionally substituted with one to five deuterium, fluoro,methoxy or OH; R^(4c) and R^(4d) of PTM-VIIa-k or PTM-VIIm for eachoccurrence are independently and optionally halogen, OH, deuterium,C₁-C₆alkyl, C₂-C₆alkenyl, —OR⁵, —(CR^(3a)R^(3b))_(n)-(3- to 6-memberedcycloalkyl), or —(CR^(3a)R^(3b))_(n)-(4- to 6-membered heterocycloalkyl)wherein said alkyl, cycloalkyl and heterocycloalkyl are each optionallyand independently substituted with one to five deuterium, halogen, OH,cyano, or C₁-C₆alkoxy; NH₂; or R^(4c) and R^(4d) taken together with thecarbons to which they are bonded form a 4- to 7-memberedheterocycloalkyl or a 3- to 7-membered cycloalkyl, wherein saidheterocycloalkyl or cycloalkyl is optionally substituted with one tothree fluoro, C₁-C₃alkyl or C₁-C₃fluoroalkyl; or R^(4a) and R^(4c) ofPTM-VIIa-k or PTM-VIIm taken together with the carbon to which they arebonded form a 4- to 7-membered heterocycloalkyl or a 3- to 7-memberedcycloalkyl, wherein said heterocycloalkyl or cycloalkyl is optionallysubstituted with one to three fluoro, C₁-C₃alkyl or C₁-C₃fluoroalkyl; R⁵of PTM-VIIa-k or PTM-VIIm is independently hydrogen or C₁-C₆alkyl,wherein said alkyl is optionally substituted with halogen, deuterium,C₁-C₆alkoxy, C₁-C₆alkylthiolyl, —NR^(11a)R^(11b), cyano, C₁-C₆alkyl orC₃-C₆cycloalkyl; or two R⁵ taken together with the oxygen atoms to whichthey are bonded form a 5- or 6-membered heterocycloalkyl; R⁶ ofPTM-VIIa-k or PTM-VIIm is —C(O)NHR⁷, CO₂R⁷ or cyano; R⁷ of PTM-VIIa-k orPTM-VIIm is hydrogen or C₁-C₆alkyl; each R⁸ of PTM-VIIa-k or PTM-VIIm isindependently hydrogen, halogen, cyano, —OR⁵, SR⁵, —C₁-C₆alkyl,C₃-C₆cycloalkyl, 3- to 10-membered heterocycloalkyl or 5- to 6-memberedheteroaryl or aryl, wherein said alkyl, cycloalkyl, heterocycloalkyl,heteroaryl or aryl is optionally substituted with one to three halogen,—NR^(11a)R^(11b), OR⁵, —SR⁵, cyano, C₁-C₃ alkyl, —C(O)R¹⁰ or oxo; R^(8′)of PTM-VIIa-k or PTM-VIIm is hydrogen, deuterium, halogen, cyano, —OR⁵,—SR⁵ or —NR^(11a)NR_(11b); R⁹ of PTM-VIIa-k or PTM-VIIm is—(CR^(3a)R^(3b))_(p)(C₁-C₃alkyl), —(CR^(3a)R^(3b))_(p)(4- to 6-memberedcycloalkyl), —(CR^(3a)R^(3b))_(p)(4- to 6-membered heterocycloalkyl) or—(CR^(3a)R^(3b))_(p)(C₅-C₉aryl), wherein said alkyl, cycloalkyl,heterocycloalkyl or aryl is each optionally substituted with fluoro orC₁-C₃alkyl; R¹⁰ of PTM-VIIa-k or PTM-VIIm is C₁-C₆alkyl, wherein saidalkyl is optionally substituted with deuterium, halogen, OH, C₁-C₆alkoxyor cyano; R^(11a) and R^(11b) of PTM-VIIa-k or PTM-VIIm are eachindependently hydrogen or C₁-C₆alkyl, wherein said alkyl is optionallysubstituted with deuterium, C₁-C₆alkoxy or cyano; and if C₂-C₆alkyl,said alkyl is optionally substituted with deuterium, C₁-C₆alkoxy, cyano,halogen or OH; m of PTM-VIIa-k or PTM-VIIm is independently 0, 1, 2 or3; n of PTM-VIIa-k or PTM-VIIm is independently 0, 1, 2 or 3; p ofPTM-VIIa-k or PTM-VIIm is independently 0 or 1; and t of PTM-VIIa-k orPTM-VIIm is 1, 2 or
 3. 10. The compound of claim 1, wherein the PTM isrepresented by Formula PTM-VIIIa, PTM-VIIIb, PTM-VIIIc, PTM-VIIId,PTM-VIIIe, or PTM-VIIIf:

wherein: Ring A of PTM-VIIIa-f is phenylene or 5- to 6-memberedheteroarylene containing 1-3 heteroatoms chosen from O, S, and N,wherein ring A is optionally substituted with lower alkyl that isfurther optionally substituted; Ring B of PTM-VIIIa-f is phenylene, 5-to 6-membered heterocycloalkylene containing 1-3 heteroatoms chosen fromO, S, and N, or 5- to 6-membered heteroarylene containing 1-3heteroatoms chosen from O, S, and N, wherein ring B is optionallysubstituted with lower alkyl or lower alkyloxyalkyl, either of which isis further optionally substituted; R² of PTM-VIIIa-f is chosen fromhydrogen and lower alkyl; R³ of PTM-VIIIa-f is chosen from hydrogen,lower alkyl optionally substituted with alkoxy, amino, N-(alkyl)amino,N,N-(dialkyl)amino, or phenyl, heterocycloalkyl, and heteroaryl, whereinphenyl, heterocycloalkyl, and heteroaryl are optionally substituted withone or two groups independently chosen from lower alkyl and whereinalkoxy is optionally substituted with tri(alkyl)silyl; R⁴ of PTM-VIIIa-fis chosen from heteroarylene and arylene, each of which is optionallysubstituted, or R⁴ and R³ of PTM-VIIIa-f taken together with thenitrogen to which they are bound, form an optionally substituted 3- to7-membered heterocycloalkyl ring, or R⁴ of PTM-VIIIa-f is an alkylenechain having 1-3 carbon atoms that is optionally substituted with one ortwo groups independently chosen from lower alkyl and cycloalkyl, each ofwhich groups is optionally substituted with hydroxyl or alkoxy, or R⁴ ofPTM-VIIIa-f is absent; R⁵ of PTM-VIIIa-f is chosen from C(O)NR⁵¹, NR⁵²,and O, or R⁵ is absent, provided that if R⁴ is absent, then R⁵ isabsent; R⁶ of PTM-VIIIa-f is an alkylene or alkenylene chain having oneor two double bonds, wherein the alkylene or alkenylene chain has 2 to10 carbon atoms, the alkylene or alkenylene chain is optionallysubstituted with one or two groups independently chosen from loweralkyl, cycloalkyl and phenyl, each of which groups is optionallysubstituted with hydroxyl, alkoxy, —C(O)OR⁸⁵, —C(O)NR⁸²R⁸³, benzoyl, andbenzyl, further wherein one or two of the carbon atoms in the alkyleneor alkenylene chain is optionally replaced by an O, S, SO, SO₂,C(O)NR⁵¹, or NR⁶¹, and wherein one of the carbon atoms in the alkyleneor alkenylene chain, is optionally connected by the nitrogen atom ofC(O)NR⁵¹ or NR⁶¹ to form a 5- to 7-membered ring, which may further besubstituted with oxo, wherein two of the carbon atoms in the alkylene oralkenylene chain, are optionally connected by a two or three carbon atomalkylene or alkenylene chain to form a 5- to 7-membered ring; R⁷ ofPTM-VIIIa-f is chosen from NR⁷¹ and O, or R⁷ is absent; R²¹ ofPTM-VIIIa-f is chosen from hydrogen and lower alkyl optionallysubstituted with lower alkoxy, wherein lower alkoxy is optionallysubstituted with tri(alkyl)silyl; R⁴¹ of PTM-VIIIa-f is independentlychosen from heterocycloalkyl, lower alkyl optionally substituted with—C(O)OR⁹, amino, N-(alkyl)amino, N,N-(dialkyl)amino, cycloalkyl, orheterocycloalkyl, —C(O)OR⁹, hydroxyl, and —C(O)NR¹⁰R¹¹, wherein R⁹ ischosen from hydrogen and lower alkyl, R¹⁰ and R¹¹ are independentlyhydrogen and lower alkyl, or R¹⁰ and R¹¹, together with the nitrogen towhich they are bound form a heterocycloalkyl, and each lower alkyl,cycloalkyl and heterocycloalkyl is optionally substituted with one, two,or three groups independently chosen from —C(O)OR⁹, lower alkyl, loweralkoxy, hydroxyl, halogen, amino, N-(alkyl)amino, N,N-(dialkyl)amino,and heterocycloalkyl; R⁵¹ of PTM-VIIIa-f is chosen from hydrogen andlower alkyl; R⁵² of PTM-VIIIa-f is chosen from hydrogen, lower alkyl,and —C(O)OR⁸¹; R⁶¹ of PTM-VIIIa-f is chosen from hydrogen, lower alkyl,—(CH₂)_(n)C(O)OR⁸¹, (CH₂)_(n)C(O)NR⁸²R⁸³, —C(O)R⁸⁴,—C(O)(CH₂)_(p)NR⁸²C(O)OR⁸¹, —C(O)(CH₂)_(p)NR⁸²R⁸³; R⁷¹ of PTM-VIIIa-f ischosen from hydrogen, lower alkyl, and —C(O)OR⁸¹; R⁸¹ of PTM-VIIIa-f ishydrogen or lower alkyl; R⁸² of PTM-VIIIa-f is hydrogen or lower alkyl,R⁸³ of PTM-VIIIa-f is hydrogen or lower alkyl, R⁸⁴ of PTM-VIIIa-f ishydrogen, lower alkyl, C₃-C₆cycloalkyl or tetrahydropyran, wherein thelower alkyl is optionally substituted with hydroxy or —C(O)OR⁸¹; R⁸⁵ ofPTM-VIIIa-f is hydrogen, lower alkyl, or benzyl, n of PTM-VIIIa-f is 0,1, 2, or 3; p of PTM-VIIIa-f is 1 or 2; and Z of PTM-VIIIa-f is chosenfrom O, S, and NR²¹.
 11. The compound of claim 1, wherein PTM isrepresented by Formula PTM-IXa, PTM-IXb, PTM-IXc, PTM-IXd, PTM-IXe,PTM-IXf, PTM-IXg, PTM-IXh, PTM-IXi, PTM-IXj, PTM-IXk, PTM-IXl, orPTM-IXm:

wherein: Ring A of PTM-IXa-m is selected from phenyl and 5- or6-membered heteroaryl; Ring B of PTM-IXa-m is selected from phenyl and5- or 6-membered heteroaryl; Ring C of PTM-IXa-m is selected from a 5-or 6-membered cycloalkyl or cycloheteroalkyl; Rind D of PTM-IXa-mselected from phenyl, 5-membered aryl or heteroaryl, 6-member aryl orheteroaryl, 5-membered cycloalkyl or cycloheteroalkyl, or 6-memberedcycloalkyl or cycloheteroalkyl; n of PTM-IXa-m is 0, 1, or 2; p ofPTM-IXa-m is 0, 1, or 2; one of W and X of PTM-IXa-m is N, and the otherof W and X is C; Y of PTM-IXa-m is N or C—R²; R¹ of PTM-IXa-m isselected from C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl, 3-to6-membered saturated heterocyclyl, halo, —CN, —C(R^(1a))═NR(OR^(1a)),—C(R^(1a))═N(R^(1a)), —C(O)R^(1a), C(O)₂R^(1a), —C(O)N(R^(1a))₂, —NO₂,—N(R^(1a))₂, —N(R^(1a))C(O)R^(1a), —N(R^(1a))C(O)₂R^(1a),N(R^(1a))C(O)N(R^(1a))₂, —N(R^(1a))S(O)₂R^(1a), —OR^(1a), —OC(O)R^(1a),—OC(O)N(R^(1a))₂, —SR^(1a), —S(O)R^(1a), S(O)₂R^(1a), —S(O)N(R^(1a))₂,and —S(O)₂N(R^(1a))₂, wherein said C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₃₋₆cycloalkyl, and 3-to 6-membered saturated heterocyclyl areoptionally substituted with one or more R¹⁰; or two R¹ substituents,together with their intervening atoms, form a C₅₋₇cycloalkyl or asaturated 5- to 7-membered heterocyclic ring, wherein saidC₅₋₇cycloalkyl or a saturated 5- to 7-membered heterocyclic ring areoptionally substituted with one or more R¹⁵; R^(1a) of PTM-IXa-m in eachoccurrence is independently selected from H, C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, 3- to 6-membered monocyclic carbocyclyl, and 3- to6-membered monocyclic heterocyclyl wherein said C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, 3- to 6-membered monocyclic carbocyclyl, and 3- to6-membered monocyclic heterocyclyl in each occurrence are optionally andindependently substituted with one or more R¹⁰; R¹⁰ of PTM-IXa-m in eachoccurrence is independently selected from ĈaUcyl, C₂₋₆alkenyl,C₂₋₆alkynyl, 3- to 6-membered carbocyclyl, 3-to 6-membered heterocyclyl,halo, —CN, —C(R^(10a))═NR(OR^(10a)), —C(R^(10a))═N(R^(11a)),—C(O)R^(10a), —C(O)₂R^(10a), —C(O)N(R^(10a))₂, —NO₂, N(R^(10a))₂,—N(R^(10a))C((O)R^(10a), —N(R^(10a))C(O)₂R^(10a),—N(R^(10a))C(O)N(R^(10a))₂, —N(R^(10a))S(O)₂R^(10a), —OR¹⁰,—OC(O)R^(10a)—OC(O)N(R^(10a))₂, —SR^(10a), —S(O)R^(10a), —S(O)₂R^(10a),—S(O)N(R^(10a))₂, and —S(O)₂N(R^(10a))₂—; R^(10a) of PTM-IXa-m in eachoccurrence is independently selected from H and C₁₋₆alkyl, wherein saidC₁₋₆alkyl is optionally substituted with one or more halo; R¹⁵ ofPTM-IXa-m in each occurrence is independently selected from C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, 3- to 6-membered carbocyclyl, 3-to 6-memberedheterocyclyl, halo, —CN, —C(R^(15a))═NR(OR^(15a)),—C(R^(15a))═N(R^(15a)), —C(O)R^(15a), —C(O)₂R^(15a), —C(O)N(R^(15a))₂,—NO₂, —N(R^(15a))₂, —N(R^(15a))C(O)R^(15a), —N(R^(15a))C(O)₂R^(15a),—N(R^(15a))C(O)N(R^(15a))₂, —N(R^(15a))S(O)₂R^(15a), —OR^(15a),—OC(O)R^(15a), —OC(O)N(R^(15a))₂, —SR^(15a), —S(O)R^(15a),—S(O)₂R^(15a), —S(O)N(R^(15a))₂, and —S(O)₂N(R^(15a))₂; R^(15a) ofPTM-IXa-m in each occurrence is independently selected from H andC₁₋₆alkyl, wherein said C₁₋₆alkyl is optionally substituted with one ormore halo; R² of PTM-IXa-m is selected from H, C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, 3- to 7-membered carbocyclyl, 3-to 7-membered heterocyclyl,halo, —CN, —C(R^(2a))═NR(OR^(2a)), C(R^(2a))═N(R^(2a)), —C(O)R^(2a),—C(O)₂R^(2a), —C(O)N(R^(2a))₂, —NO₂, —N(R^(2a))₂, —N(R^(2a))C(O)R^(2a),—N(R^(2a))C(O)₂R^(2a), —N(R^(2a))C(O)N(R^(2a))₂, —N(R^(2a))S(O)₂R^(2a),—OR^(2a), —OC(O)R^(2a), OC(O)N(R^(2a))₂, —SR^(2a), —S(O)R^(2a),—S(O)₂R^(2a), —S(O)N(R^(2a))₂, and —S(O)₂N(R^(2a))₂, wherein saidC₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, 3-to 7-membered carbocyclyl, and3-7 membered heterocyclyl are optionally substituted with one or moreR²⁰; R^(2a) of PTM-IXa-m in each occurrence is independently selectedfrom H and C₁₋₆alkyl, wherein said C₁₋₆alkyl in each occurrence isoptionally and independently substituted with one or more R²⁰; R²⁰ ofPTM-IXa-m in each occurrence is independently selected from C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₇cycloalkyl, 3-to 7-membered saturatedheterocyclyl, halo, —CN, —C(R^(20a))═NR(OR^(20a)),—C(R^(20a))═N(R^(20a)), —C(O)R^(20a), —C(O)₂R^(20a), —C(O)N(R^(20a))₂,—NO₂, —N(R^(20a))₂, —N(R^(20a))C(O)R^(20a), —N(R^(20a))C(O)₂R^(20a),—N(R^(20a))C(O)N(R^(20a))₂, —N(R^(20a))S(O)₂R^(20a), —OR^(20a),—OC(O)R^(20a), —OC(O)N(R^(20a))₂, —SR^(20a), —S(O)R^(20a),—S(O)₂R^(20a), —S(O)N(R^(20a))₂, and —S(O)₂N(R^(20a))₂, wherein saidC₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₇cycloalkyl, and 3-7 memberedsaturated heterocyclyl in each occurrence are optionally andindependently substituted with one or more R²⁵; R^(20a) of PTM-IXa-m ineach occurrence is independently selected from H and C₁₋₆alkyl, whereinsaid C₁₋₆alkyl is optionally substituted with R²⁵; R²⁵ of PTM-IXa-m isselected from halo and —OR^(25a); R^(25a) of PTM-IXa-m is selected fromH and C₁₋₆alkyl; R³ of PTM-IXa-m is selected from C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl, 3-to 6-membered saturatedheterocyclyl, halo, —CN, —C(R^(3a))═NR(OR^(3a)), —C(R^(3a))═N(R^(3a)),C(O)R^(3a), —C(O)₂R^(3a), —C(O)N(R^(3a))₂, —NO₂, —N(R^(3a))₂,—N(R^(3a))C(O)R^(3a), —N(R^(3a))C(O)₂R^(3a), N(R^(3a))C(O)N(R^(3a))₂,—N(R^(3a))S(O)₂R^(3a), —OR^(3a), —OC(O)R^(3a), —OC(O)N(R^(3a))₂,—SR^(3a), —S(O)R^(3a), —S(O)₂R^(3a), —S(O)N(R^(3a))₂, and—S(O)₂N(R^(3a))₂, wherein said C₁₋₆alkyl, C₂₋₆alkenyl, C₂-6alkynyl,C₃₋₆cycloalkyl, and 3-to 6-membered saturated heterocyclyl areoptionally substituted with one or more R³⁰; R^(3a) of PTM-IXa-m in eachoccurrence is independently selected from H, C₁₋₆alkyl, 3- to 6-memberedcarbocyclyl, and 3- to 6-membered heterocyclyl, wherein said C₁₋₆alkyl,3- to 6-membered carbocyclyl, and 3- to 6-membered heterocyclyl in eachoccurrence are optionally and independently substituted with one or moreR³⁰; R³⁰ of PTM-IXa-m in each occurrence is independently selected fromC₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, 3- to 6-membered carbocyclyl, 3-to6-membered heterocyclyl, halo, —CN, —C(R^(30a))═NR(OR^(30a)),—C(R^(30a))═N(R^(30a)), —C(O)R^(30a), —C(O)₂R^(30a), —C(O)N(R^(30a))₂,—NO₂, —N(R^(30a))₂, —N(R^(30a))C(O)R^(30a), —N(R^(30a))C(O)₂R^(30a),—N(R^(30a))C(O)N(R^(30a))₂, —N(R^(30a))S(O)₂R^(30a), —OR^(30a),—OC(O)R^(30a), —OC(O)N(R^(30a))₂, —SR^(30a), —S(O)R^(30a),—S(O)₂R^(30a), —S(O)N(R^(30a))₂, and —S(O)₂N(R^(30a))₂, wherein saidC₁₋₃alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, 3-6 membered carboyclyl, 3- to6-membered heterocyclyl in each occurence are optionally andindependently substituted with one or more R³⁵; R^(30a) of PTM-IXa-m ineach occurrence is independently selected from H and C₁₋₆alkyl, whereinsaid C₁₋₆alkyl is optionally substituted with one or more R³⁵; R³⁵ ofPTM-IXa-m in each occurrence is independently selected from halo and—OR^(35a); R^(35a) of PTM-IXa-m in each occurrence is independentlyselected from H and C₁₋₆alkyl; R^(35b) of PTM-IXa-m in each occurrenceis independently selected from H, halo, optionally substituted alkoxy(e.g., optionally substituted C1-C4 alkoxy), optionally substitutedalkyl (e.g., C1-C4 alkyl optionally substituted with halo or hydroxy),hydroxyalkyl (e.g. C1-C4 hydroxyalkyl), or haloalkyl (e.g., C1-C4haloalkyl); R^(35c) of PTM-IXa-m in each occurrence is independentlyselected from halo or haloalkyl (e.g., C1-C4 haloalkyl); R⁴ of PTM-IXa-mis selected from H, halo, C₁₋₆alkyl, N(R^(4a))₂, and —OR^(4a); andR^(4a) of PTM-IXa-m in each occurrence is independently selected from Hand C₁₋₆alkyl.
 12. The compound of claim 1, wherein the PTM isrepresented by Formula PTM-Xa, PTM-Xb, PTM-Xc, PTM-Xd, PTM-Xe, PTM-Xf,or PTM-Xg:

wherein:

A of PTM-Xa-g is

 or A of PTM-X is a triazole optionally substituted by 0-2 R X ofPTM-Xa-g is N or C—R⁷; R of PTM-Xa-g is hydrogen, R¹, halogen, cyano,nitro, —OR¹, —C(═O)—R¹, —C(═O)O—R¹, —C(═O)NR¹¹—R¹, —S(═O)₂—R¹,—NR¹¹C(═O)—R, —NR¹¹C(═O)NR¹¹R¹¹, —NR¹¹C(═O)NR¹¹R¹, —NR¹¹C(═O)O—R¹,—NR¹¹S(═O)₂R¹, —NR¹¹R¹¹, or NR¹¹R¹; R¹ of PTM-Xa-g is C₁₋₆ alkylsubstituted with 0-4 R^(1a), C₁₋₆ haloalkyl, C₂₋₆ alkenyl substitutedwith 0-3 R^(1a), C₂₋₆ alkynyl substituted with 0-3 R^(1a), C₃₋₁₀cycloalkyl substituted with 0-3 R^(1a)C₆₋₁₀ aryl substituted with 0-3R^(1a), a 5-10 membered heterocycle containing 1-4 heteroatoms selectedfrom N, O, and S, substituted with 0-3 R^(1a), or a 5-10 memberedheteroaryl containing 1-4 heteroatoms selected from N, O, and S,substituted with 0-3 R^(1a); R^(1a) of PTM-Xa-g is hydrogen, ═O, F, Cl,Br, OCF₃, CN, NO₂, —(CH₂)_(r)OR^(b), —(CH₂)_(r)SR^(b),(CH₂)_(r)C(O)R^(b), —(CH₂)_(r)C(O)OR^(b), —(CH₂)_(r)OC(O)R^(b),—(CH₂)_(r)NR¹¹R¹¹, (CH₂)_(r)C(O)NR¹¹R¹¹, —(CH₂)_(r)NR^(b)C(O)R^(c),—(CH₂)_(r)NR^(b)C(O)OR^(c), NR^(b)C(O)NR¹¹R¹¹, S(O)_(p)NR¹¹R¹¹,NR^(b)S(O)_(p)R^(c), —S(O)R^(c), —S(O)₂R^(c), C₁₋₆ alkyl substitutedwith 0-2 R^(a), C₁₋₆ haloalkyl, —(CH₂)_(r)-3-14 membered carbocyclesubstituted with 0-3 R^(a), or —(CH₂)_(r)-5-7 membered heterocycle orheteroaryl, each comprising carbon atoms and 1-4 heteroatoms selectedfrom N, O, and S(O)_(p) substituted with 0-3 R^(a); R² of PTM-Xa-g isC₆₋₁₀ aryl substituted with 0-4 R^(2a), a 5-10 membered heterocyclecontaining 1-4 heteroatoms selected from N, O, and S, substituted with1-4 R^(2a), or a 5-10 membered heteroaryl containing 1-4 heteroatomsselected from N, O, and S, substituted with 0-4 R^(2a); R^(2a) ofPTM-Xa-g at each occurrence is independently selected from hydrogen, ═O,halo, OCF₃, CN, NO₂, —(CH₂)_(r)OR^(b), —(CH₂)_(r)SR^(b),—(CH₂)_(r)C(O)R^(b), —(CH₂)_(r)C(O)OR^(b), (CH₂)_(r)OC(O)R^(b),—(CH₂)_(r)NR¹¹R¹¹, —(CH₂)_(r)C(O)NR¹¹R¹¹, —(CH₂)_(r)NR^(b)C(O)R^(c),(CH₂)_(r)NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹R¹, —S(O)_(p)NR¹¹R¹¹,—NR^(b)S(O)_(p)R^(c), —S(O)R^(c), S(O)₂R^(c), C₁₋₆ alkyl substitutedwith 0-2 R^(a), C₁₋₆ haloalkyl, —(CH₂)_(r)-3-14 membered carbocyclesubstituted with 0-1 R^(a), or —(CH₂)_(r)-5-7 membered heterocycle orheteroaryl, each comprising carbon atoms and 1-4 heteroatoms selectedfrom N, O, and S(O)_(p) substituted with 0-2 R^(a); R³ of PTM-Xa-g isC₁₋₆alkyl substituted with 0-3 R^(3a), C₁₋₆ haloalkyl, C₂₋₆ alkenylsubstituted with 0-3 R^(3a), C₂₋₆ alkynyl substituted with 0-3 R^(3a),C₃₋₁₀ cycloalkyl substituted with 0-3 R^(3a)C₆₋₁₀ aryl substituted with0-3 R^(3a), a 5-10 membered heterocyclyl containing 1-4 heteroatomsselected from N, O, and S, substituted with 0-3 R^(3a) or a 5-10membered heteroaryl containing 1-4 heteroatoms selected from N, O, andS, substituted with 0-3 R^(3a); R^(3a) of PTM-Xa-g is hydrogen, ═O, F,Cl, Br, OCF₃, CN, NO₂, —(CH₂)_(r)OR^(b), —(CH₂)_(r)SR^(b),(CH₂)_(r)C(O)R^(b), —(CH₂)_(r)C(O)OR^(b), —(CH₂)_(r)OC(O)R^(b),—(CH₂)_(r)NR¹¹R¹¹, (CH₂)_(r)C(O)NR¹¹R¹¹, —(CH₂)_(r)NR^(b)C(O)R^(c),—(CH₂)_(r)NR^(b)C(O)OR^(c), NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹,NR^(b)S(O)_(p)R^(c), —S(O)R^(c), —S(O)₂R^(c), C₁₋₆ alkyl substitutedwith 0-2 R^(a), C₁₋₆haloalkyl, —(CH₂)_(r)-3-14 membered carbocyclesubstituted with 0-1 R^(a), or —(CH₂)_(r)-5-7 membered heterocycle orheteroaryl, each comprising carbon atoms and 1-4 heteroatoms selectedfrom N, O, and S(O)_(p) substituted with 0-1 R^(a); R⁴ and R⁵ ofPTM-Xa-g are independently selected from hydrogen, C₁₋₄ alkylsubstituted with 0-1 R^(f), (CH₂)-phenyl substituted with 0-3 R^(d), anda —(CH₂)-5-7 membered heterocycle comprising carbon atoms and 1-4heteroatoms selected from N, O, and S(O)_(p); R⁶ and R⁷ of PTM-Xa-g areindependently at each occurrence is selected from hydrogen, ═O, F, Cl,Br, OCF₃, CN, NO₂, —(CH₂)_(r)OR^(b), —(CH₂)_(r)SR^(b),—(CH₂)_(r)C(O)R^(b), (CH₂)_(r)C(O)OR^(b), —(CH₂)_(r)OC(O)R^(b),—(CH₂)_(r)NR¹¹R¹¹, —(CH₂)_(r)C(O)NR¹¹R¹¹, (CH₂)_(r)NR^(b)C(O)R^(c),—(CH₂)_(r)NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹⁰R¹¹, —S(O)_(p)NR¹¹R¹¹,NR^(b)S(O)_(p)R^(c), —S(O)R^(c), —S(O)₂R^(c), C₁₋₆alkyl substituted with0-2 R^(a), C₁₋₆haloalkyl, (CH₂)_(r)-3-14 membered carbocycle substitutedwith 0-3 R^(a), or —(CH₂)_(r)-5-7 membered heterocycle or heteroaryl,each comprising carbon atoms and 1-4 heteroatoms selected from N, O, andS(O)_(p) substituted with 0-3 R^(a), provided R⁶ and R⁷ are not bothhydrogen; R¹¹ of PTM-Xa-g at each occurrence is independently hydrogen,R^(e), C₁₋₄ alkyl substituted with 0-1 R^(f), CH₂-phenyl substitutedwith 0-3 R^(d), or —(CH₂)-5-7 membered heterocycle or heteroaryl, eachcomprising carbon atoms and 1-4 heteroatoms selected from N, O, andS(O)_(p) substituted with 0-3 R^(d); or R¹¹ and along with another R¹¹,R¹, or R² on the same nitrogen atom may join to form an optionallysubstituted heterocycle; R^(a) of PTM-Xa-g is hydrogen, F, Cl, Br, OCF₃,CF₃, CHF₂, CN, NO₂, —(CH₂)_(r)OR^(b), (CH₂)_(r)SR^(b),—(CH₂)_(r)C(O)R^(b), —(CH₂)_(r)C(O)OR^(b), —(CH₂)_(r)OC(O)R^(b),—(CH₂)_(r)NR¹¹R¹¹, (CH₂)_(r)C(O)NR¹¹R¹¹, —(CH₂)_(r)NR^(b)C(O)R^(c),—(CH₂)_(r)NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹,NR^(b)S(O)_(p)R^(c), —S(O)R^(c), —S(O)₂R^(c), C₁₋₆ alkyl substitutedwith 0-1 R^(f), C₁₋₆ haloalkyl, —(CH₂)_(r)-3-14 membered carbocycle, or—(CH₂)_(r)-5-7 membered heterocycle or heteroaryl, each comprisingcarbon atoms and 1-4 heteroatoms selected from N, O, and S(O)_(p); ortwo R^(a) on adjacent or the same carbon atom form a cyclic acetal ofthe formula —O—(CH₂)_(n)—O—, or —O—CF₂—O—, wherein n is selected from 1or 2; R^(b) of PTM-Xa-g is hydrogen, R^(e) of PTM-X, C₁₋₆ alkylsubstituted with 0-2 R^(d), C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl substitutedwith 0-2 R^(d), or (CH₂)_(r)-phenyl substituted with 0-3 R^(d); R^(e) isC₁-6 alkyl substituted with 0-1 R^(f), C₃₋₆ cycloalkyl, or(CH₂)_(r)-phenyl substituted with 0-3 R^(f); R^(c) of PTM-Xa-g isC₁₋₆alkyl, C₃₋₆cycloalkyl, or (CH₂)_(r)-phenyl substituted with 0-3R^(f); R^(d) of PTM-Xa-g is hydrogen, F, Cl, Br, OCF₃, CF₃, CN, NO₂,—OR^(e), —(CH₂)_(r)C(O)R^(e), NR^(e)R^(e), —NR^(e)C(O)OR^(c), C₁₋₆alkyl, or (CH₂)_(r)-phenyl substituted with 0-3 R^(f); R^(e) of PTM-Xa-gis selected from hydrogen, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, and(CH₂)_(r)-phenyl substituted with 0-3 R^(f); R^(f) of PTM-Xa-g ishydrogen, halo, NH₂, OH, or O(C₁₋₆alkyl); p of PTM-Xa-g is 0, 1, or 2; rof PTM-Xa-g is 0, 1, 2, 3, or 4; and m of PTM-Xa-g is 0, 1, or
 2. 13.The compound of claim 1, wherein the PTM is represented by FormulaPTM-XIa, PTM-XIb, or PTM-XIc:

wherein: X of PTM-XIa-c is NH or O; b of PTM-XIa-c is 0 or 1; n ofPTM-XIa-c is 0, 1, 2, 3 or 4; R₁ and R₂ of PTM-XIa-c are independentlyH, (C₁-C₄)alkyl and heterocyclyl, or R₁ and R₂ can be taken togetherwith the nitrogen to which they are attached to form a monocyclic orbicyclic (fused, bridged or spirocyclic) heterocycle containing 3-8carbon atoms optionally containing, in addition to the nitrogen, one ortwo additional heteroatoms selected from N, O and S, said alkyl andheterocycle are optionally substituted with one or more substituentsselected from R_(a); R³ of PTM-XIa-c is (C₁-C₄)alkyl wherein twoadjacent alkyl groups can join together and form a bridged moiety of 3-6carbon atoms; R₄ of PTM-XIa-c is absent, halo or O_(b)(C₁-C₄)alkyl; R₅of PTM-XIa-c is selected from halo, CN, O(C₁-C₄)alkyl, C₁-C₄ alkyl andC₂-C₄ alkenyl which are optionally substituted with one or moresubstituents selected from R_(b) or R₅ is aryl or heteroaryl eachoptionally substituted with one or more substitutents selected fromR_(b); R₆ of PTM-XIa-c is absent, halo, or O(C₁-C₄)alkyl; R_(a) ofPTM-XIa-c is halo, oxo, OH, O_(b)(C₁-C₄)alkyl, C(O)O_(b)(C₁-C₆)alkyl,(C═O)_(b)heterocyclyl, CF₃, SO₂H, SO₂(C₁-C₄)alkyl, C(O)C₁-C₄alkyl, orheterocyclyl, wherein said alkyl can come together with another alkyl toform a bridged moiety and said alkyl and heterocyclyl are optionallysubstituted with one or more substituents independently selected from Fand (C₁-C₄)alkyl; and R_(b) of PTM-XIa-c is independently selected fromOH, halo, CHF₂, CF₃, COOH, SO₂(C₁-C₄)alkyl, C(O)C₁-C₄alkyl, (C═O)NH₂,O_(b)(C₁-C₄)alkyl, aryl, heterocyclyl, CN, C(O)N(R^(c))₂, N(R^(c))₂,wherein the R^(c) and alkyl are optionally substituted with OH,O(C₁-C₄)alkyl and heterocyclyl; and R^(c) of PTM-XIa-c is independentlyselected from H, SO₂(C₁-C₄)alkyl, or C₁-C₄ alkyl.
 14. The compound ofclaim 1, wherein the PTM is represented by Formula PTM-XIIa, PTM-XIIb,PTM-XIIc, PTM-XIId, PTM-XIIe, or PTM-XIIf:

wherein: B of PTM-XIIa-f is CH, N or S; D of PTM-XII is CH or N; E ofPTM-XII is CH or N; F of PTM-XII is CH or N; G of PTM-XII is CH or N;and J of PTM-XII is C or N, wherein when B is S then D is CH, E is N, Fis CH, G is N and J is C; X of PTM-XIIa-f is O, S, CH₂ or N; m ofPTM-XIIa-f is 0 or 1; n of PTM-XIIa-f is 0, 1, 2, 3 or 4; Ring A ofPTM-XIIa-f is aryl, heterocyclyl, pyridinyl, pyrazolyl, thiophenyl,furanyl or phenyl; R₁ of PTM-XIIa-f is independently selected from(C₁-C₄)alkyl, (C₃-C₆)cycloalkyl, heterocyclyl, CF₃, CHF₂, CN, halo,pyrimidine, piperidine and phenyl, each optionally substituted with(C₁-C₄)alkyl, OH, CH₃, OCH₃, halo, O(C₁-C₄)alkyl, methyl-piperidine,S(O)₂R^(c), C(O)N(R^(b))₂, or C(O)O(C₁-C₄)alkyl; R₂ of PTM-XIIa-f isabsent or H and R₃ is independently selected from: (C₁-C₄)alkyl,(C₁-C₆)alkyl, (C₃-C₈)cycloalkyl, heterocyclyl, pyranyl, cyclopentyl,cyclohexyl, cycloheptyl, thiopyranyl, pyrazolyl, piperidinyl,morpholinyl, piperazinyl, each optionally substituted with one or moresubstituents independently selected from halo, OH, oxo, N(R_(b))₂,oxopyrrolidinyl, or morpholinyl, or R₂ and R₃ can be taken together withthe nitrogen to which they are attached to form a heterocyclyl,piperazine or morpholine, each optionally substituted with one or moresubstituents selected from oxo and R_(a); R₄ of PTM-XIIa-f isindependently H or methyl; R_(a) of PTM-XIIa-f is independently selectedfrom (C₁-C₄)alkyl, (C₃-C₆)cycloalkyl, cyclopropyl, CF₃, F, CHF₂, OH,halo and NH₂, said alkyl optionally substituted with (C₃-C₆)cycloalkyland CF₃; and R_(b) of PTM-XIIa-f is independently selected from H and(C₁-C₄)alkyl; and R_(c) of PTM-XIIa-f is methyl.
 15. The compound ofclaim 1, wherein the PTM is represented by Formula PTM-XIIIa, PTM-XIIIb,PTM-XIIIc, PTM-XIIId, PTM-XIIIe, PTM-XIIIf, PTM-XIIIg, PTM-XIIIh,PTM-XIIIi, or PTM-XIIIj:

wherein: Ring Z₁ of PTM-XIIIa-j is an optionally substituted heteroaryl;Ring Z₂ of PTM-XIIIa-j is a optionally substituted heterocycloalkyl,optionally substituted heteroaryl or a direct bond; R₁ of PTM-XIIIa-j isoptionally substituted alkyl, optionally substituted hydroxyalkyl,cyano, —NR_(a)R_(b), optionally substituted cycloalkyl, optionallysubstituted aryl or optionally substituted heterocyclyl; wherein thesubstituent, at each occurrence, independently is alkyl, alkoxy,halogen, hydroxyl, hydroxyalkyl, amino, aminoalkyl, nitro, cyano,haloalkyl, haloalkoxy, —OCO—CH₂—O-alkyl, —OP(O)(O-alkyl)₂ or—CH₂—OP(O)(O-alkyl)₂; R₂ of PTM-XIIIa-j, at each occurrence,independently is an optionally substituted group selected from alkyl,cycloalkyl, or cycloheteroalkyl; wherein the substituent, at eachoccurrence, is independently halogen, alkoxy, hydroxyl, hydroxyalkyl,haloalkyl or haloalkoxy; R_(2a) of PTM-XIIIa-j is an H or optionallysubstituted alkyl (e.g., optionally substituted C₁-C₄ alkyl); R₃ ofPTM-XIIIa-j, at each occurrence, independently is hydrogen, halogen,alkyl, haloalkyl, haloalkoxy, alkoxy, —NR_(a)R_(b), hydroxyl orhydroxyalkyl; R₄ of PTM-XIIIa-j at each occurrence is independently ishalogen, cyano, an unsubstituted or a singly or multiply, identically ordifferently substituted C1-C5-alkyl or an unsubstituted or a singly ormultiply, identically or differently substituted C3-C6-cycloalkyl (e.g.,the substituents of the alkyl or cycloalkyl may be selected from thegroup of halogen and hydroxyl); R₅ of PTM-XIIIa-j at each occurrence isindependently is hydrogen, halogen or an unsubstituted orpoly-halogen-substituted C1-C5-alkyl; R₆ of PTM-XIIIa-j at eachoccurrence is independently optionally substituted C1-C6-alkyl (e.g.,C1-C6-alkyl radical unsubstituted, monobustituted or polysubstitutedidentically or differently by halogen, hydroxyl, an unsubstituted ormono- or poly-halogen-substituted C3-C6-cycloalkyl, or an R⁹, R¹⁰SO₂,R¹⁰SO or R¹¹O radical, or a group selected from:

 wherein * represents the bonding site of the group to the rest of themolecule); R₇ and R₈ of PTM-XIIIa-j at each occurrence is independentlyselected from hydrogen or C1-C6-alkyl (e.g., both may be H or a C1-C6alkyl, including the same C1-C6 alkyl); R₉ of PTM-XIIIa-j is anunsubstituted or mono- or di-methyl-substituted monocyclic saturatedheterocycle having 4 to 6 ring atoms, which contains a heteroatom or aheterogroup from the group of O, S, SO and SO₂; R₁₀ of PTM-XIIIa-j is aC1-C6-alkyl, where the C1-C5-alkyl radical is unsubstituted or mono- orpolysubstituted identically or differently by halogen, hydroxyl orC3-C5-cycloalkyl; or R₁₀ is C3-C6-cycloalkyl R₁₁ of PTM-XIIIa-j is anoptionally substituted C1-C6-alkyl (e.g., a C1-C6-alkyl radical isunsubstituted or mono- or polysubstituted identically or differently by,e.g., halogen); R_(a) of PTM-XIIIa-j is hydrogen or alkyl; R_(b) ofPTM-XIIIa-j is hydrogen, alkyl, acyl, hydroxyalkyl, —SO₂-alkyl oroptionally substituted cycloalkyl; R₁₂ of PTM-XIIIa-j is optionallysubstituted C1-C5 alkyl, optionally substituted methyl, optionallysubstituted ethyl, optionally substituted cyloalky, or

R₁₃ of PTM-XIIIa-j is H or methyl; R₁₄ of PTM-XIIIa-j is an optionallysubstituted linear or branched alkyl (e.g., optionally substitutedlinear or branched C1-C8 alkyl), optionally substituted amide,carboxylic group, optionally substituted cycloalkyl, optionallysubstituted heterocycloalkyl, optionally substituted aryl (e.g.,optionally substituted C5-C7 aryl), optionally substituted heteroaryl(e.g., optionally substituted C5-C7 heteroaryl), —SO₂-alkyl, —SO2H,—O-alkyl, —O-aryl, —O-heteroaryl, optionally substituted urea group; Wand Y of PTM-XIIIa-j are selected from C and N with the proviso that oneis N and one is C; X of PTM-XIIIa-j is CH or N; “m” of PTM-XIIIa-j is 1or 2; and “n” of PTM-XIIIa-j is 1 or
 2. 16. The compound according toclaim 1, wherein ULM is a Von Hippel-Lindau (VHL) ligase-binding moiety(VLM) with a chemical structure represented by:

wherein: X¹, X² are each independently selected from the group of abond, O, NR^(Y3), CR^(Y3)R^(Y4), C═O, C═S, SO, and SO₂; R^(Y3), R^(Y4)are each independently selected from the group of H, linear or branchedC₁₋₆ alkyl, optionally substituted by 1 or more halo, optionallysubstituted C₁₋₆ alkoxyl (e.g., optionally substituted by 0-3 R^(p)groups); R^(P) is 0, 1, 2, or 3 groups, each independently selected fromthe group H, halo, —OH, C₁₋₃ alkyl, C═O; W³ is selected from the groupof an optionally substituted T, an optionally substituted-T-N(R^(1a)R^(1b))X³, optionally substituted -T-N(R^(1a)R^(1b)),optionally substituted -T-Aryl, an optionally substituted -T-Heteroaryl,an optionally substituted T-biheteroaryl, an optionally substituted-T-Heterocycle, an optionally substituted -T-biheterocycle, anoptionally substituted —NR¹-T-Aryl, an optionally substituted—NR¹-T-Heteroaryl or an optionally substituted —NR¹-T-Heterocycle; X³ isC═O, R¹, R^(1a), R^(1b); each of R¹, R^(1a), R^(1b) is independentlyselected from the group consisting of H, linear or branched C₁-C₆ alkylgroup optionally substituted by 1 or more halo or —OH groups, R^(Y3)C═O,R^(Y3)C═S, R^(Y3)SO, R^(Y3)SO₂, N(R^(Y3)R^(Y4))C═O, N(R^(Y3)R^(Y4))C═S,N(R^(Y3)R^(Y4))SO, and N(R^(Y3)R^(Y4))SO₂; T is selected from the groupof an optionally substituted alkyl, —(CH₂)_(n)— group, wherein each oneof the methylene groups is optionally substituted with one or twosubstituents selected from the group of halogen, methyl, optionallysubstituted alkoxy, a linear or branched C₁-C₆alkyl group optionallysubstituted by 1 or more halogen, C(O) NR₁R^(1a), or NR¹R^(1a) or R¹ andR^(1a) are joined to form an optionally substituted heterocycle, or —OHgroups or an amino acid side chain optionally substituted; and n is 0 to6, W⁴ is

R_(14a), R_(14b), are each independently selected from the group of H,haloalkyl, or optionally substituted alkyl; W⁵ is selected from thegroup of a phenyl or a 5-10 membered heteroaryl, R₁₅ is selected fromthe group of H, halogen, CN, OH, NO₂, N R_(14a)R_(14b), OR^(14a),CONR_(14a)R_(14b), NR_(14a)COR_(14b), SO₂NR_(14a)R_(14b), NR_(14a)SO₂R_(14b), optionally substituted alkyl, optionally substitutedhaloalkyl, optionally substituted haloalkoxy, optionally substitutedaryl, optionally substituted heteroaryl, optionally substitutedcycloalkyl, or optionally substituted cycloheteroalkyl; and wherein thedashed line indicates the site of attachment of at least one PTM,another ULM (ULM′) or a chemical linker moiety coupling at least one PTMor a ULM′ or both to ULM.
 17. The compound according to claim 1, whereinULM is a Von Hippel-Lindau (VHL) ligase-binding moiety (VLM) with achemical structure represented by:

wherein: W³ is selected from the group of an optionally substitutedaryl, optionally substituted heteroaryl, or

R₉ and R₁₀ are independently hydrogen, optionally substituted alkyl,optionally substituted cycloalkyl, optionally substituted hydroxyalkyl,optionally substituted heteroaryl, or haloalkyl, or R₉, R₁₀, and thecarbon atom to which they are attached form an optionally substitutedcycloalkyl; R₁₁ is selected from the group of an optionally substitutedheterocyclic, optionally substituted alkoxy, optionally substitutedheteroaryl, optionally substituted aryl,

R₁₂ is selected from the group of H or optionally substituted alkyl; R₁₃is selected from the group of H, optionally substituted alkyl,optionally substituted alkylcarbonyl, optionally substituted(cycloalkyl)alkylcarbonyl, optionally substituted aralkylcarbonyl,optionally substituted arylcarbonyl, optionally substituted(heterocyclyl)carbonyl, or optionally substituted aralkyl; R_(14a),R_(14b), are each independently selected from the group of H, haloalkyl,or optionally substituted alkyl; W⁵ is selected from the group of aphenyl or a 5-10 membered heteroaryl, R₁₅ is selected from the group ofH, halogen, CN, OH, NO₂, N R_(14a)R_(14b), OR^(14a), CONR_(14a)R_(14b),NR_(14a)COR_(14b), SO₂NR_(14a)R_(14b), NR_(14a) SO₂R_(14b), optionallysubstituted alkyl, optionally substituted haloalkyl, optionallysubstituted haloalkoxy optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted cycloalkyl, or optionallysubstituted cycloheteroalkyl; R₁₆ is independently selected from thegroup of halo, optionally substituted alkyl, optionally substitutedhaloalkyl, hydroxy, or optionally substituted haloalkoxy; o is 0, 1, 2,3, or 4; R₁₈ is independently selected from the group of H, halo,optionally substituted alkoxy, cyano, optionally substituted alkyl,haloalkyl, haloalkoxy or a linker; and p is 0, 1, 2, 3, or 4, andwherein the dashed line indicates the site of attachment of at least onePTM, another ULM (ULM′) or a chemical linker moiety coupling at leastone PTM or a ULM′ or both to ULM.
 18. The compound according to claim 1,wherein the ULM has a chemical structure selected from the group of:

wherein: R₁ is H, ethyl, isopropyl, tert-butyl, sec-butyl, cyclopropyl,cyclobutyl, cyclopentyl, or cyclohexyl; optionally substituted alkyl,optionally substituted hydroxyalkyl, optionally substituted heteroaryl,or haloalkyl; R_(14a) is H, haloalkyl, optionally substituted alkyl,methyl, fluoromethyl, hydroxymethyl, ethyl, isopropyl, or cyclopropyl;R₁₅ is selected from the group consisting of H, halogen, CN, OH, NO₂,optionally substituted heteroaryl, optionally substituted aryl;optionally substituted alkyl, optionally substituted haloalkyl,optionally substituted haloalkoxy, optionally substituted cycloalkyl, oroptionally substituted cycloheteroalkyl; X is C, CH₂, or C═O R₃ isabsent or an optionally substituted 5 or 6 membered heteroaryl; andwherein the dashed line indicates the site of attachment of at least onePTM, another ULM (ULM′) or a chemical linker moiety coupling at leastone PTM or a ULM′ or both to the ULM.
 19. The compound according toclaim 1, wherein the ULM comprises a group according to the chemicalstructure:

wherein: R_(14a) is H, haloalkyl, optionally substituted alkyl, methyl,fluoromethyl, hydroxymethyl, ethyl, isopropyl, or cyclopropyl; R9 is H;R10 is H, ethyl, isopropyl, tert-butyl, sec-butyl, cyclopropyl,cyclobutyl, cyclopentyl, or cyclohexyl; R11 is

 optionally substituted heteroaryl,

p is 0, 1, 2, 3, or 4; and each R₁₈ is independently halo, optionallysubstituted alkoxy, cyano, optionally substituted alkyl, haloalkyl,haloalkoxy or a linker; R12 is H, C═O; R13 is H, optionally substitutedalkyl, optionally substituted alkylcarbonyl, optionally substituted(cycloalkyl)alkylcarbonyl, optionally substituted aralkylcarbonyl,optionally substituted arylcarbonyl, optionally substituted(heterocyclyl)carbonyl, or optionally substituted aralkyl; R₁₅ isselected from the group consisting of H, halogen, Cl, CN, OH, NO₂,optionally substituted heteroaryl, optionally substituted aryl;

 and wherein the dashed line indicates the site of attachment of atleast one PTM, another ULM (ULM′) or a chemical linker moiety couplingat least one PTM or a ULM′ or both to the ULM.
 20. The compoundaccording to claim 1, wherein the ULM is a cereblon E3 ligase-bindingmoiety (CLM) selected from the group consisting of a thalidomide,lenalidomide, pomalidomide, analogs thereof, isosteres thereof, orderivatives thereof.
 21. The compound according to claim 20, wherein theCLM has a chemical structure represented by:

wherein: W is selected from the group consisting of CH₂, CHR, C═O, SO₂,NH, and N-alkyl; each X is independently selected from the groupconsisting of O, S, and H₂; Y is selected from the group consisting ofCH₂, —C═CR′, NH, N-alkyl, N-aryl, N-hetaryl, N-cycloalkyl,N-heterocyclyl, O, and S; Z is selected from the group consisting of O,S, and H₂; G and G′ are independently selected from the group consistingof H, optionally substituted linear or branched alkyl, OH, R′OCOOR,R′OCONRR″, CH₂-heterocyclyl optionally substituted with R′, and benzyloptionally substituted with R′; Q₁, Q₂, Q₃, and Q₄ represent a carbon Csubstituted with a group independently selected from R′, N or N-oxide; Ais independently selected from the group H, optionally substitutedlinear or branched alkyl, cycloalkyl, C₁ and F; R comprises —CONR′R″,—OR′, —NR′R″, —SR′, —SO₂R′, —SO₂NR′R″, —CR′R″—, —CR′NR′R″—,(—CR′O)_(n′)R″, -aryl, -hetaryl, optionally substituted linear orbranched -alkyl, -cycloalkyl, -heterocyclyl, —P(O)(OR′)R″, —P(O)R′R″,—OP(O)(OR′)R″, —OP(O)R′R″, —Cl, —F, —Br, —I, —CF₃, —CN, —NR′SO₂NR′R″,—NR′CONR′R″, —CONR′COR″, —NR′C(═N—CN)NR′R″, —C(═N—CN)NR′R″,—NR′C(═N—CN)R″, —NR′C(═C—NO₂)NR′R″, —SO₂NR′COR″, —NO₂, —CO₂R′,—C(C═N—OR′)R″, —CR′═CR′R″, —CCR′, —S(C═O)(C═N—R′)R″, —SF₅ and —OCF₃; R′and R″ are independently selected from the group consisting of a bond,H, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclic, —C(═O)R,heterocyclyl, each of which is optionally substituted;

represents a bond that may be stereospecific ((R) or (S)) ornon-stereospecific; and R_(n) comprises from 1 to 4 independentlyselected functional groups or atoms, for example, O, OH, N, C1-C6 alkyl,C1-C6 alkoxy, -alkyl-aryl (e.g., an -alkyl-aryl comprising at least oneof C1-C6 alkyl, C4-C7 aryl, or a combination thereof), aryl (e.g., C5-C7aryl), amine, amide, or carboxy, n′ is an integer from 1-10 (e.g., 1-4,1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), and wherein when n is 1, R_(n) ismodified to be covalently joined to the linker group (L), and when n is2, 3, or 4, then one R_(n) is modified to be covalently joined to thelinker group (L), and any other R_(n) is optionally modified to becovalently joined to a PTM, a CLM, a second CLM having the same chemicalstructure as the CLM, a CLM′, a second linker, or any multiple orcombination thereof.
 22. The compound according to claim 20, wherein theCLM has a chemical structure represented by:

wherein: W is independently selected from the group CH2, C═O, NH, andN-alkyl; R is independently selected from a H, methyl, or optionallysubstituted linear or branched C1-C6 alkyl;

represents a bond that may be stereospecific ((R) or (S)) ornon-stereospecific; and Rn comprises from 1 to 4 independently selectedfunctional groups or atoms, for example, O, OH, N, C1-C6 alkyl, C1-C6alkoxy, -alkyl-aryl (e.g., an -alkyl-aryl comprising at least one ofC1-C6 alkyl, C4-C7 aryl, or a combination thereof), aryl (e.g., C5-C7aryl), amine, amide, or carboxy, and optionally, one of which ismodified to be covalently joined to a PTM, a chemical linker group (L),a CLM (or CLM′) or combination thereof.
 23. The compound of any ofclaims 1-15, wherein the ULM is a (MDM2) binding moiety (MLM) with achemical moiety selected from the group consisting of a substitutedimidazolines, a substituted spiro-indolinones, a substitutedpyrrolidines, a substituted piperidinones, a substituted morpholinones,a substituted pyrrolopyrimidines, a substituted imidazolopyridines, asubstituted thiazoloimidazoline, a substituted pyrrolopyrrolidinones,and a substituted isoquinolinones.
 24. The compound according to claim1, wherein the ULM is a IAP E3 ubiquitin ligase binding moiety (ILM)comprising the amino acids alanine (A), valine (V), proline (P), andisoleucine (I) or their unnatural mimetics.
 25. The compound accordingto claim 24, wherein the ULM is a IAP E3 ubiquitin ligase binding moiety(ILM) comprising a AVPI tetrapeptide fragment or derivative thereof. 26.The compound according to claim 1, wherein the linker (L) comprises achemical structural unit represented by the formula:-(A^(L))_(q)-, wherein: (A^(L))_(q) is a group which is connected to atleast one of ULM moiety, PTM moiety, or a combination thereof; and q isan integer greater than or equal to 1, each A is independently selectedfrom the group consisting of, a bond, CR^(L1)R^(L2), O, S, SO, SO₂,NR^(L3), SO₂NR^(L3), SONR^(L3), CONR^(L3), NR^(L3)CONR^(L4),NR^(L3)SO₂NR^(L4), CO, CR^(L1)═CR^(L2), C≡C, SiR^(L1)R^(L2), P(O)R^(L1),P(O)OR^(L1), NR^(L3)C(═NCN)NR^(L4), NR^(L3)C(═NCN),NR^(L3)C(═CNO₂)NR^(L4), C₃₋₁₁cycloalkyl optionally substituted with 0-6R^(L1) and/or R^(L2) groups, C₃₋₁₁heteocyclyl optionally substitutedwith 0-6 R^(L1) and/or R^(L2) groups, aryl optionally substituted with0-6 R^(L1) and/or R^(L2) groups, heteroaryl optionally substituted with0-6 R^(L1) and/or R^(L2) groups, where R^(L1) or R^(L2), eachindependently are optionally linked to other groups to form cycloalkyland/or heterocyclyl moiety, optionally substituted with 0-4 R^(L5)groups; and R^(L1), R^(L2), R^(L3), R^(L4) and R^(L5) are, eachindependently, H, halo, C₁₋₈alkyl, OC₁₋₈alkyl, SC₁₋₈alkyl, NHC₁₋₈alkyl,N(C₁₋₈alkyl)₂, C₃₋₁₁cycloalkyl, aryl, heteroaryl, C₃₋₁₁heterocyclyl,OC₁₋₈cycloalkyl, SC₁₋₈cycloalkyl, NHC₁₋₈cycloalkyl, N(C₁₋₈cycloalkyl)₂,N(C₁₋₈cycloalkyl)(C₁₋₈alkyl), OH, NH₂, SH, SO₂C₁₋₈alkyl,P(O)(OC₁₋₈alkyl)(C₁₋₈alkyl), P(O)(OC₁₋₈alkyl)₂, CC—C₁₋₈alkyl, CCH,CH═CH(C₁₋₈alkyl), C(C₁₋₈alkyl)═CH(C₁₋₈alkyl),C(C₁₋₈alkyl)═C(C₁₋₈alkyl)₂, Si(OH)₃, Si(C₁₋₈alkyl)₃, Si(OH)(C₁₋₈alkyl)₂,COC₁₋₈alkyl, CO₂H, halogen, CN, CF₃, CHF₂, CH₂F, NO₂, SF₅,SO₂NHC₁₋₈alkyl, SO₂N(C₁₋₈alkyl)₂, SONHC₁₋₈alkyl, SON(C₁₋₈alkyl)₂,CONHC₁₋₈alkyl, CON(C₁₋₈alkyl)₂, N(C₁₋₈alkyl)CONH(C₁₋₈alkyl),N(C₁₋₈alkyl)CON(C₁₋₈alkyl)₂, NHCONH(C₁₋₈alkyl), NHCON(C₁₋₈alkyl)₂,NHCONH₂, N(C₁₋₈alkyl)SO₂NH(C₁₋₈alkyl), N(C₁₋₈alkyl) SO₂N(C₁₋₈alkyl)₂, NHSO₂NH(C₁₋₈alkyl), NH SO₂N(C₁₋₈alkyl)₂, NH SO₂NH₂.
 27. The compoundaccording to claim 26, wherein the linker (L) comprises a grouprepresented by a general structure selected from the group consistingof:—N(R)—(CH2)_(m)—O(CH2)_(n)—O(CH2)_(o)—O(CH2)_(p)—O(CH2)_(q)—O(CH2)_(r)-OCH2-,—O—(CH2)_(m)O(CH2)_(n)—O(CH2)_(o)—O(CH2)_(p)—O(CH2)_(q)—O(CH2)_(r)-OCH2-,—O(CH2)_(m)O(CH2)_(n)—O(CH2)_(o)—O(CH2)_(p)—O(CH2)_(q)—O(CH2)_(r)—O—;—N(R)—(CH2)_(m)O(CH2)_(n)O(CH2)_(o)O(CH2)_(p)O(CH2)_(q)O(CH2)_(r)O—;—(CH2)_(m)O(CH2)_(n)O(CH2)_(o)O(CH2)_(p)—O(CH2)_(q)—O(CH2)_(r)—O—;—(CH2)_(m)O(CH2)_(n)O(CH2)_(o)O(CH2)_(p)—O(CH2)_(q)—O(CH2)_(r)-OCH2-;

wherein each m, n, o, p, q, and r is independently 0, 1, 2, 3, 4, 5, 6,with the proviso that when the number is zero, there is no N—O or O—Obond, R is selected from the group H, methyl and ethyl, and X isselected from the group H and F;


28. The compound according to claim 26, wherein the linker (L) isselected from the group consisting of:


29. The compound according to claim 26, wherein the linker (L) isselected from the group consisting of:

wherein each m, n, o, p, q, r, and s is independently 0, 1, 2, 3, 4, 5,6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or
 20. 30. Thecompound according to claim 26, wherein the linker is selected from:


31. The compound according to claim 1, wherein the linker (L) comprisesthe following chemical structure:

wherein: W^(L1) and W^(L2) are each independently a 4-8 membered ringwith 0-4 heteroatoms, optionally substituted with RQ, each RQ isindependently a H, halo, OH, CN, CF3, C1-C6 alkyl (linear, branched,optionally substituted), C1-C6 alkoxy (linear, branched, optionallysubstituted), or 2 RQ groups taken together with the atom they areattached to, form a 4-8 membered ring system containing 0-4 heteroatoms;Y^(L1) is each independently a bond, C1-C6 alkyl (linear, branched,optionally substituted) and optionally one or more C atoms are replacedwith O; or C1-C6 alkoxy (linear, branched, optionally substituted); n is0-10; and a dashed line indicates the attachment point to the PTM or ULMmoieties.
 32. The compound according to claim 1, wherein the linker (L)comprises the following chemical structure:

wherein: W^(L1) and W^(L2) are each independently aryl, heteroaryl,cyclic, heterocyclic, C₁₋₆ alkyl, bicyclic, biaryl, biheteroaryl, orbiheterocyclic, each optionally substituted with R^(Q), each R^(Q) isindependently a H, halo, OH, CN, CF₃, hydroxyl, nitro, C≡CH, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁-C₆ alkyl (linear, branched, optionallysubstituted), C₁-C₆ alkoxy (linear, branched, optionally substituted),OC₁₋₃alkyl (optionally substituted by 1 or more —F), OH, NH₂,NR^(Y1)R^(Y2), CN, or 2 R^(Q) groups taken together with the atom theyare attached to, form a 4-8 membered ring system containing 0-4heteroatoms; Y^(L1) is each independently a bond, NR^(YL1), O, S,NR^(YL2), CR^(YL1)R^(YL2), C═O, C═S, SO, SO₂, C₁-C₆alkyl (linear,branched, optionally substituted) and optionally one or more C atoms arereplaced with O; C₁-C₆ alkoxy (linear, branched, optionallysubstituted); Q^(L) is a 3-6 membered alicyclic or aromatic ring with0-4 heteroatoms, optionally bridged, optionally substituted with 0-6R^(Q), each R^(Q) is independently H, C₁₋₆ alkyl (linear, branched,optionally substituted by 1 or more halo, C₁₋₆ alkoxyl), or 2 R^(Q)groups taken together with the atom they are attached to, form a 3-8membered ring system containing 0-2 heteroatoms); R^(YL1), R^(YL2) areeach independently H, OH, C₁₋₆ alkyl (linear, branched, optionallysubstituted by 1 or more halo, C₁₋₆ alkoxyl), or R¹, R² together withthe atom they are attached to, form a 3-8 membered ring systemcontaining 0-2 heteroatoms); n is 0-10; and a dashed line indicates theattachment point to the PTM or ULM moieties.
 33. The compound accordingto claim 31, wherein the linker (L) is selected from the groupconsisting of:


34. The compound according to claim 1, wherein the linker (L) is apolyethylenoxy group optionally substituted with aryl or phenylcomprising from 1 to 10 ethylene glycol units.
 35. The compoundaccording to claim 1, wherein the compound is selected from Table 4,including salts, prodrugs, polymorphs, analogs, derivatives, anddeuterated forms thereof.
 36. The compound according to claim 1, whereinat least one of: the PTM is selected from Table 6, the linker isselected from Table 7, the ULM is selected from Table 8, or acombination thereof.
 37. The compound according to claim 1, wherein thePTM is selected from:


38. A composition comprising an effective amount of a bifunctionalcompound of claim 1, and a pharmaceutically acceptable carrier.
 39. Thecomposition of claim 38, wherein the composition further comprises atleast one of additional bioactive agent or another bifunctional compoundof claim
 1. 40. The composition of claim 39, wherein the additionalbioactive agent is anti-neurodegenerative agent, an anti-inflammatoryagent, and/or an anti-cancer agent.
 41. A method for treating a diseaseor disorder in a subject, the method comprising administering acomposition comprising a pharmaceutically acceptable carrier and aneffective amount of at least one compound of claim 1 to a subject inneed thereof, wherein the compound is effective in treating orameliorating at least one symptom of the disease or disorder.
 42. Themethod of claim 41, wherein the disease or disorder is associated withtau accumulation and aggregation.
 43. The method of claim 41, whereinthe disease or disorder is a neurodegenerative disease or disorder, aninflammatory disease or disorder and/or a cancer associated with IRAK-4accumulation and aggregation.
 44. The method of claim 43, wherein thecancer is squamous-cell carcinoma, basal cell carcinoma, adenocarcinoma,hepatocellular carcinomas, and renal cell carcinomas, cancer of thebladder, bowel, breast, cervix, colon, esophagus, head, kidney, liver,lung, neck, ovary, pancreas, prostate, and stomach; leukemias; benignand malignant lymphomas, particularly Burkitt's lymphoma andNon-Hodgkin's lymphoma; benign and malignant melanomas;myeloproliferative diseases; sarcomas, including Ewing's sarcoma,hemangiosarcoma, Kaposi's sarcoma, liposarcoma, myosarcomas, peripheralneuroepithelioma, synovial sarcoma, gliomas, astrocytomas,oligodendrogliomas, ependymomas, gliobastomas, neuroblastomas,ganglioneuromas, gangliogliomas, medulloblastomas, pineal cell tumors,meningiomas, meningeal sarcomas, neurofibromas, and Schwannomas; bowelcancer, breast cancer, prostate cancer, cervical cancer, uterine cancer,lung cancer, ovarian cancer, testicular cancer, thyroid cancer,astrocytoma, esophageal cancer, pancreatic cancer, stomach cancer, livercancer, colon cancer, melanoma; carcinosarcoma, Hodgkin's disease,Wilms' tumor and teratocarcinomas. Additional cancers which may betreated using compounds according to the present disclosure include, forexample, T-lineage Acute lymphoblastic Leukemia (T-ALL), T-lineagelymphoblastic Lymphoma (T-LL), Peripheral T-cell lymphoma, Adult T-cellLeukemia, Pre-B ALL, Pre-B Lymphomas, Large B-cell Lymphoma, BurkittsLymphoma, B-cell ALL, Philadelphia chromosome positive ALL andPhiladelphia chromosome positive CML.
 45. The method of claim 44,wherein the inflammatory disease or disorder is selected from the groupconsisting of ocular allergy, conjunctivitis, keratoconjunctivitissicca, vernal conjunctivitis, allergic rhinitis, autoimmunehematological disorders (e.g. hemolytic anemia, aplastic anemia, purered cell anemia and idiopathic thrombocytopenia), systemic lupuserythematosus, rheumatoid arthritis, polychondritis, scleroderma,Wegener granulamatosis, dermatomyositis, chronic active hepatitis,myasthenia gravis, Steven-Johnson syndrome, idiopathic sprue, autoimmuneinflammatory bowel disease (e.g. ulcerative colitis and Crohn'sdisease), irritable bowel syndrome, celiac disease, periodontitis,hyaline membrane disease, kidney disease, glomerular disease, alcoholicliver disease, multiple sclerosis, endocrine opthalmopathy, Grave'sdisease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis,primary biliary cirrhosis, uveitis (anterior and posterior), Sjogren'ssyndrome, interstitial lung fibrosis, psoriatic arthritis, systemicjuvenile idiopathic arthritis, nephritis, vasculitis, diverticulitis,interstitial cystitis, glomerulonephritis (e.g. including idiopathicnephrotic syndrome or minimal change nephropathy), chronic granulomatousdisease, endometriosis, leptospirosis renal disease, glaucoma, retinaldisease, headache, pain, complex regional pain syndrome, cardiachypertrophy, muscle wasting, catabolic disorders, obesity, fetal growthretardation, hypercholesterolemia, heart disease, chronic heart failure,mesothelioma, anhidrotic ecodermal dysplasia, Behcet's disease,incontinentia pigmenti, Paget's disease, pancreatitis, hereditaryperiodic fever syndrome, asthma, acute lung injury, acute respiratorydistress syndrome, eosinophilia, hypersensitivities, anaphylaxis,fibrositis, gastritis, gastroenteritis, nasal sinusitis, ocular allergy,silica induced diseases, chronic obstructive pulmonary disease (COPD),cystic fibrosis, acid-induced lung injury, pulmonary hypertension,polyneuropathy, cataracts, muscle inflammation in conjunction withsystemic sclerosis, inclusion body myositis, myasthenia gravis,thyroiditis, Addison's disease, lichen planus, appendicitis, atopicdermatitis, asthma, allergy, blepharitis, bronchiolitis, bronchitis,bursitis, cervicitis, cholangitis, cholecystitis, chronic graftrejection, colitis, conjunctivitis, cystitis, dacryoadenitis,dermatitis, juvenile rheumatoid arthritis, dermatomyositis,encephalitis, endocarditis, endometritis, enteritis, enterocolitis,epicondylitis, epididymitis, fasciitis, Henoch-Schonlein purpura,hepatitis, hidradenitis suppurativa, immunoglobulin A nephropathy,interstitial lung disease, laryngitis, mastitis, meningitis, myelitismyocarditis, myositis, nephritis, oophoritis, orchitis, osteitis,otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis,pleuritis, phlebitis, pneumonitis, pneumonia, polymyositis, proctitis,prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis,stomatitis, synovitis, tendonitis, tonsillitis, ulcerative colitis,vasculitis, vulvitis, alopecia areata, erythema multiforma, dermatitisherpetiformis, scleroderma, vitiligo, hypersensitivity angiitis,urticaria, bullous pemphigoid, pemphigus vulgaris, pemphigus foliaceus,paraneoplastic pemphigus, epidermolysis bullosa acquisita, acute andchronic gout, chronic gouty arthritis, psoriasis, psoriatic arthritis,rheumatoid arthritis, Cryopyrin Associated Periodic Syndrome (CAPS) andosteoarthritis.